Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][N:20]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37].O1CCOCC1>O1CCOCC1.CCOCC>[ClH:37].[ClH:37].[C:31]1([S:28]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:15]=3[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21]2)(=[O:30])=[O:29])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(-c2cccs2)cn3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1cc(-c2cccs2)c2c(N3CCNCC3)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 4-(7-Benzenesulfonyl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.23 mmol) in 2 mL dioxane was added 1.5 mL 4M HCl/dioxane. The reaction mixture was stirred at room temperature 6 hours, after which it was diluted with ether, and the solids were isolated by filtration through a fritted funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to give 7-Benzenesulfonyl-4-piperazin-1-yl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (110 mg, 95%) as a yellow powder. LCMS (APCI+) m/z 426 [M+H]+; Rt: 1.95 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:19]([O:34][CH3:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:19]([O:34][CH3:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1C1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}piperidine-1-carboxylate (0.0446 g, 0.0937 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-yl)benzofuran-3(2H)-one (0.0312 g, 88%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:29](=[O:30])[NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)OCC1CCSc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (283 mg, 1.36 mmol) in 17 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.21 ml, 1.5 mmol) and cyclohexyl isocyanate (682 μl, 5.56 mmol). The mixture was stirred at 80° C. for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 190 mg (42%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH3:24])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Reactant: CI
Product: Cc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1
Yield: 89 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazole (0.25 g) and methyl iodide (0.06 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.23 g, 89%) as a colorless powder.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:39]#[N:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-:42].OO>CO>[Si:1]([O:8][C@@H:9]([C:39](=[O:42])[NH2:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)O[Si](C)(C)C(C)(C)C)CC4)CC1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
A 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]-2-cyanoethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (2.2 g, 3.75 mmol, 1.00 equiv) in 20 mL of methanol was added LiOH (315 mg), followed by addition of H2O2 (30%, 3 mL) via syringe at 0° C. with vigorous stirring. The resulting solution was stirred for 3 h at 20° C. The reaction was then quenched by the addition of 50 mL of saturated aqueous Na2SO3, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with 2×30 mL of brine, and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) to afford the desired tert-butyl N-(4-[[(3R)-3-[(2R)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (0.7 g) as a white solid. MS: m/z 605 (M+H)+, 627 (M+Na)+.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])(=[O:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:38][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)[CH:39]=[CH:40][CH:41]=1)(=[O:33])[CH3:32]
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(Nc3cccc4c3ccn4C)n2)c1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsOH*H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (20 mg). MS found for C22H21N7O2 as (M+H)+ 416.3. λ=211.3, 250.9.
Reaction SMILES: [ClH:1].C([N:9]([CH2:14][C@@H:15]1[CH2:17][C@H:16]1[CH3:18])[CH2:10][CH2:11][O:12][CH3:13])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[ClH:1].[CH3:13][O:12][CH2:11][CH2:10][NH:9][CH2:14][C@@H:15]1[CH2:17][C@H:16]1[CH3:18]
Reactant: COCCN(Cc1ccccc1)C[C@@H]1C[C@H]1C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: COCCNC[C@@H]1C[C@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans N-benzyl-2-methoxy-N-[(2-methylcyclopropyl)methyl]ethanamine hydrochloride (16 g, 59.3 mmol) in EtOH (400 mL), degassed with Argon, was added Pd(OH)2 (830 mg, 20%), and the mixture was stirred under 1 atm H2, at room temperature for 4 h. The reaction mixture was purged with N2, filtered on celite, under N2, concentrated in vacuo, and dried under vacuum over P2O5 to give trans (2-methoxyethyl)[(2-methylcyclopropyl)methyl]amine hydrochloride as a white foam. 1H NMR (400 MHz, CDCl3) δ 9.46 (bs, 2H), 3.84 (t, J=5.1 Hz, 2H), 3.40 (s, 3H), 3.23 (bt, J=5.1 Hz, 2H), 3.08-2.88 (m, 2H), 1.09 (d, J=6.1 Hz, 3H), 1.02-0.91 (m, 1H), 0.86-0.78 (m, 1H), 0.65-0.57 (m, 1H), 0.50-0.42 (m, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: Fc1ncccc1I
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
Hydrazine hydrate (12.50 mL, 256 mmol) was added dropwise to a solution of 2-fluoro-3-iodopyridine (preparation 26a, 5.72 g, 25.7 mmol) in ethanol (43 mL) and the resulting mixture was stirred at room temperature for 24 hours and then at 35° C. for a further 24 hours. The solvent was then evaporated in vacuo and water was added. The white solid that formed was filtered, washed with water and dried to yield the title compound (2.78 g, 46%) as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccnc1C
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccnc1CBr

Procedure:
Ethyl 2-methylpyridine-3-carboxylate is refluxed with N-bromosuccinimide in carbon tetrachloride with 1% equivalent dibenzyl peroxide to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1.C(=O)([O-])[O-].[K+].[K+].[Na+].[I-].[Cl-].[Na+]>CN(C=O)C>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)C[C@H](C)N1
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
0.8 g of 2-chloro-5-(trifluoromethyl)pyridine (compound of formula (VII)), 0.5 g of cis-2,6-dimethylpiperazine (compound of formula (VI)), 0.67 g of potassium carbonate and 0.3 g of NaI are placed in 8 ml of DMF. The reaction is performed in a CEMdiscover microwave initiator for 30 minutes at 160° C. The mixture is then poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 1.1 g of an oily material corresponding to the title product are isolated.
Reaction SMILES: C[O:2][C:3](=[O:25])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:24][C:14]1[CH:13]=[C:12](/[C:4](=[CH:5]\[CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)/[C:3]([OH:25])=[O:2])[CH:17]=[CH:16][C:15]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[N:19]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1Cl
Temperature: 47.5 °C
Yield: 100.9 %

Procedure:
A solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (209 mg, 0.58 mmol) in ethanol (3 mL) was treated with a 1N aqueous sodium hydroxide solution (1.2 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (10 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (203 mg, 99%) as a brown solid: FAB-HRMS m/e calcd for C17H19ClN4O2 (M+H)+ 347.1275, found 347.1283.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:36])[N:18]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C@@H:19]4[C@H:24]([C:25]=3[OH:26])[C@@H:23]3[CH2:27][C@H:20]4[CH2:21][CH2:22]3)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:14])(=[O:15])[N:11]=[C:10]([C:16]3[C:17](=[O:36])[N:18]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[C@@H:19]4[C@H:24]([C:25]=3[OH:26])[C@@H:23]3[CH2:27][C@H:20]4[CH2:21][CH2:22]3)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (1R,2S,7R,8S)-5-(7-azidomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.10 g, 0.19 mmol) in ethanol (6 mL) and ethyl acetate (3 mL) was added 10% palladium on carbon (10 mg). The mixture was degassed and stirred under an atmosphere of hydrogen gas (balloon) overnight. The resulting mixture was diluted with N,N-dimethylformamide (10 mL) and filtered through a pad of Celite. The organic was concentrated in vacuo to afford the crude product, (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (95 mg, 0.19 mmol, 100%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([N+:18]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([NH2:18])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A suspension of (4-tert-butyl-3-nitro-phenyl)-carbamic acid tert-butyl ester (3.0 g, 10.19 mol) and 10% Pd—C (1 g) in MeOH (40 mL) was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether-EtOAc, 5:1) to give (3-amino-4-tert-butyl-phenyl)-carbamic acid tert-butyl ester (D-10) as a brown oil (2.5 g, 93%). 1H NMR (CDCl3) δ 7.10 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 6.50-6.53 (m, 1H), 6.36 (s, 1H), 3.62 (br s, 2H), 1.50 (s, 9H), 1.38 (s, 9H); ESI-MS 528.9 m/z (2M+H+).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]>C(O)(=O)C>[Br:1][C:15]1[C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:5][CH2:3][CH3:4])[CH:16]=1
Reactant: CCOC(=O)c1cc(OCC)ccc1OCC
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(Br)cc1OCC
Reaction time: 1 h
Yield: 31.9 %

Procedure:
A solution of bromine (0.338 mL, 6.60 mmol) in acetic acid (6 mL) was added dropwise to a mixture of ethyl 2,5-diethoxybenzoate (1.36 mL, 6.02 mmol) and acetic acid (24 mL) cooled in a water bath. After stirring 1 h, more bromine (0.102 mL, 1.99 mmol) was added dropwise to the reaction mixture. After stirring an additional 4 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with 10% diethyl ether in hexanes) to give ethyl 4-bromo-2,5-diethoxybenzoate as an off-white solid (0.610 g, 32%).
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[C:47]1([C:53]2[CH:66]=[CH:65][C:56]([CH2:57][S:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:55][CH:54]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:59]([S:58][CH2:57][C:56]1[CH:55]=[CH:54][C:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:66][CH:65]=1)[C:60]([O:62][CH2:63][CH3:64])=[O:61])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccc(-c2ccccc2)cc1
Yield: 68.6 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5.7 g), a 2M ethanolic solution of sodium ethylate (10 cc) and ethyl (4-phenylbenzylthio)acetate (5.7 g) in ethanol (50 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent, diethyl 2-dimethylamino-5-(4-phenylbenzylthio)-2,4-hexadienedioate (6 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:19]=1[NH2:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:20][C:19]3[C:18]([Cl:17])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:25])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CSC1=Nc2ccc(Cl)cc2C(=O)N(C)C1
Product: CN1CC(Nc2c(Cl)cccc2Cl)=Nc2ccc(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 20.38 g (0.08 m) of 7-chloro-3,4-dihydro-4-methyl-2-methylthio-5H-1,4-benzodiazepine-5-one and 64.81 g (0.40 m) of 2,6-dichloroaniline is stirred and heated to 225° for 11/2 hr. The reaction mixture is cooled to room temperature and crystallized from ether to give the crude product, 7-chloro-2-(2',6'-dichloroanilino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one, m.p. (230) 240°-245°. Recrystallization from acetone-ether and from methanol-isopropanol gives white solid with m.p. 247°-249.5° .
Reaction SMILES: CN(C([O:8][N:9]1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.C(ON)(C)(C)C.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH2:53][CH:54]([CH2:58][S:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:55](O)=[O:56])(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.FC(F)(F)C(O)=O>CN(C=O)C.C(#N)C.C(OCC)(=O)C>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH2:53][CH:54]([CH2:58][S:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:55]([NH:9][OH:8])=[O:56])(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1
Reactant: O=C(O)C(CSc1ccccc1)CS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CC(C)(C)ON
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=C(NO)C(CSc1ccccc1)CS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
TBTU (0,72 g) was added portionwise to a stirred solution of N-methylmorpholine (0.5 mL) and O-tert-butylhydroxylamine hydrochloride (0.43 g) and 3-[(4′-chloro[1,1′-biphenyl]-4-yl)sulfonyl]-2-[(phenylsulfanyl)methyl]-propanoic acid (0.5 g) in 20 mL of DMF and 20 mL of acetonitrile cooled at −5° C. After stirring at ambient temperature overnight, the resulting solution was diluted with ethyl acetate and sequentially washed with 0.1 M citric acid and 0.1 M NaHCO3. After drying over anhydrous sodium sulfate and removal of the solvent, the crude reaction mixture was treated with trifluoroacetic acid (10 mL) and kept aside for 6 hours. The solvent was removed and the residue was partitioned between ethyl acetate and 0.1 M NaHCO3. After drying, the solvent was evaporated off and the residue was chromatographed on silica gel eluting with chloroform/cyclohexane 2/3 to afford, after crystallization from ethyl acetate, 0.35 g of the title compound, mp . . .
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].C(N([CH2:19][CH3:20])CC)C>CO.O>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:10]3[C:19]4[C:20](=[CH:1][CH:3]=[CH:4][CH:13]=4)[CH2:6][C@H:11]3[OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O

Procedure:
12 g (68 mmol) of 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine, 18 g (136 mmol) of 1,2-indenoxide and 9,6 ml (68 mmol) of triethylamine are stirred in 95 ml methanol/water (4:1) for 14 hours at 40° C. The mixture is evaporated at 50° C. in the rotary evaporator, mixed with 200 ml icewater, rendered alkaline with sodium hydroxide solution (approximately pH 13), and the precipitate is filtered off. The filtrate is shaken out with dichloromethane and the organic phase made up to 250 ml with dichloromethane, combined with the precipitate, dried with magnesium sulfate and purified with active charcoal. 250 ml of toluene is added, dichloromethane is distilled off, the mixture is purified at the boiling point with bleaching earth (e.g. Tonsil®), evaporated to half its volume and allowed to crystallize in the refrigerator. The yield of the titel compound m.p. 200°-202° C. is 17.6 g (84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@@H:6]([NH:13]C(=O)OC(C)(C)C)[C@@H:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11].C([C@H](NC(=O)OC(C)(C)C)[C@@H](O)CCCC)C1C=CC=CC=1>>[NH2:13][C@@H:6]([C@@H:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:4]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[CH:3]=1
Reactant: CCCC[C@H](O)[C@@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Agent: CCCC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CCCC[C@H](O)[C@H](N)Cc1cc(F)cc(F)c1

Procedure:
Prepared from the Boc removal of the anti diastereoisomer tert-butyl (1R,2S)-1-(3,5-difluorobenzyl)-2-hydroxyhexylcarbamate using a similar procedure as described in intermediate I step D. ES MS (M+H)=244.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH:13]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18]
Reactant: CC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Reactant: COC(C)(OC)N(C)C
Product: CC(=CC(=O)c1cc(C)c([N+](=O)[O-])cc1C)N(C)C
Temperature: 130 °C

Procedure:
A mixture of 1-(2,5-dimethyl-4-nitrophenyl)ethanone (Step 1, 300 mg, 1.55 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (1 mL) was heated in a microwave at 130° C. for 10 min. The crude product was purified with silica gel chromatography (60% ethyl acetate in hexanes) to afford 1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one as a yellow solid.