Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:34])[CH2:32][CH3:33])(=[O:29])[CH2:27][CH3:28]>>[C:26]([O-:30])(=[O:29])[CH2:27][CH3:28].[CH2:1]([NH+:8]1[CH2:13][CH2:12][C:11]([C:21]2[NH:22][N:23]=[N:24][N:25]=2)([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:31](=[O:34])[CH2:32][CH3:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: c1ccc(CN2CCC(Nc3ccccc3)(c3nnn[nH]3)CC2)cc1
Product: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Product: CCC(=O)[O-]
Reaction time: 6 h

Procedure:
A 250 ml r.b. flask was charged with 1-benzyl-4-(1H-tetrazol-5-yl)-4-anilinopiperidine (17.7 g, 53 mmol) and propionic anhydride (95 ml). The resulting mixture was stirred at 70°-75° C. for 6 hours. Then, it was concentrated in vacuo and the crude was chromatographed (SiO2, 5-20% MeOH/CH2Cl2) to give the desired compound (14.7 g, 32 mmol) as white powder: m.p. 226-228 C; R (nujol) 1660 cm-1 ; MR (270 MHz, CDCl3) δ0.864, (t, 3H, CH3CH2CON), 1.175 (t, 3H, CH3CH2CO2H), 1.883 (q, 2H, CH3CH2CO2H), 2.113 (m, 4H), 2.395 (q, 2H, CH3CH2CO2H), 2.8-3.1 (m, 4H), 3.464 (s, 2H, benzyl CH2), 7.1 to 7.5 (complex, 10H, phenyl H's). Anal. Calcd. for C22H26N6O. C3H6O2 : C, 64.64; H, 6.94; N, 18.09. Found: C, 64.65; H, 7.00; N, 17.89. ##STR22##
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH:16]1([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2([CH3:15])[CH3:1])[CH2:19][CH2:18][CH2:17]1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C(C)(C)C1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (413 mg, 1.65 mmol) was dissolved in DCE (15 mL). TEA (1.148 mL, 8.23 mmol) was added, followed by cyclobutanone (231 mg, 3.29 mmol) and sodium triacetoxyborohydride (524 mg, 2.47 mmol). The reaction mixture was stirred for 5 h and a few drops of acetic acid were added. The reaction mixture was heated at 40° C. for 4 days, cooled to rt, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give a dark yellow oil. The crude title compound was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9](O)=[O:10].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9]([N:3]([O:4][CH3:5])[CH3:2])=[O:10]
Reactant: Nc1c(Cl)ccc(Cl)c1C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Yield: 73 %

Procedure:
N,O-dimethlyhydroxylamine hydrochloride (3.28 g, 33 mmol) and 2-amino-3,6-dichlorobenzoic acid (4.76 g, 22 mmol) were dissolved in DMF (110 ml). At r.t. under nitrogen and stirring, first N-methyl morpholine (10 g, 99 mmol) and then HBTU (12.5 g, 33 mmol) were added, and the reaction was stirred at r.t. overnight. The reaction was poured onto water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was treated with heptane and little diethyl ether to yield 4 g of the product. The mother liquor was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to give another batch of the title compound as an off-white solid (5.52 g, 100%).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:55][NH:56][C:57](=[NH:59])[CH3:58]>C(Cl)Cl>[O:23]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:59]/[C:57](=[N:56]\[OH:55])/[CH3:58])=[O:19])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(=N)NO
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C/C(=N/O)NC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Reaction time: 0.33 h

Procedure:
To a suspension of the product obtained in Step A above (540 mg, 1.61 mmol) in 10 ml of CH2Cl2 there are added, in succession, 516 mg (1.61 mmol) of TBTU and then 364 μl (2.09 mmol) of DIEA. After stirring for 20 minutes, 120 mg (1.61 mmol) of N-hydroxyacetamidine are added and the reaction mixture is stirred for 1.5 hours at ambient temperature. The reaction mixture is washed with water and then with saturated NaCl solution, dried (MgSO4) and evaporated to dryness. The residue is taken up in CH2Cl2; a white precipitate forms which is filtered off to yield the expected product.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.[CH2:26]([O:28][C:29]#[CH:30])[CH3:27].N1C(C)=CC=CC=1C.O>C(#N)C.[Cu](I)I>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: C#COCC
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: I[Cu]I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.3 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (Reference Example 2) (733 mg, 2.0 mmol) was dissolved in dry acetonitrile (8 ml). Ethoxyacetylene (420 mg, 6.0 mmol), 2,6-lutidine (236 mg, 2.2 mmol) and copper iodide (38 mg, 10 mmol %) were added and the resulting mixture was stirred at room temperature for 12 hours. Water was added and the mixture was extracted with dichloromethane (3×100 ml). The combined organic layers were concentrated under vacuum and the residue was purified by flash chromatography on silica gel with 5% of methanol in dichloromethane to give the title product (666 mg).
Reaction SMILES: C1(C[O:8][C:9]([CH2:11][N:12]([CH:17]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:19]3([CH2:24][CH2:23][N:22]([C:25]([C@H:27]([NH:38][C:39](=[O:44])[C:40]([NH2:43])([CH3:42])[CH3:41])[CH2:28][C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][CH:30]=4)=[O:26])[CH2:21][CH2:20]3)[CH2:18]2)[S:13]([CH3:16])(=[O:15])=[O:14])=[O:10])C=CC=CC=1.[H][H]>CO.[Pd]>[C:9]([CH2:11][N:12]([CH:17]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:19]2([CH2:24][CH2:23][N:22]([C:25]([C@H:27]([NH:38][C:39](=[O:44])[C:40]([NH2:43])([CH3:42])[CH3:41])[CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)[CH2:18]1)[S:13]([CH3:16])(=[O:14])=[O:15])([OH:10])=[O:8]
Reactant: [H][H]
Reactant: CC(C)(N)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CC(N(CC(=O)OCc1ccccc1)S(C)(=O)=O)c1ccccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CC(N(CC(=O)O)S(C)(=O)=O)c1ccccc12

Procedure:
A solution of ca. 25 mg of N-[1(R)-[[3-[N-[[[phenylmethoxy]carbonyl]methyl]-N-(methylsulfonyl)amino]-2,3-dihydrospiro[1H-indene-1,4'-piperidin]-1'-yl]carbonyl]-2-(indole-3-yl)ethyl]-2-amino-2-methylpropanamide from Example 149, Step D, in 0.5 mL of methanol containing 25 mg of 10% Pd/C, is shaken under a 50 psi atmosphere of hydrogen over night. After filtration and taking the filtrate to dryness under reduced pressure, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1ncccc1N

Procedure:
A solution of 6-chloro-3-nitropicolinamide (2.00 g, 9.91 mmol) in EtOAc/MeOH (1:1, 100 mL) is hydrogenated over 5% Pd-C (0.40 g) at 60 psi for 6 days, with additions of fresh catalyst after 2 and 4 days. After removal of the catalyst by filtration the solution is concentrated to dryness, to give 3-aminopicolinamide as an orange oil, which is used directly in the next step. The crude product is stirred under reflux with triethyl orthoformate (50 mL) for 42 h, during which time a tan precipitate forms. After cooling, the solid is filtered off, washed well with petroleum ether, and dried under vacuum to give 3H-pyrido[3,2-d]pyrimidin-4-one (1.27g, 87%), mp 343-345° C. [Price, C. C. and Curtin, D. Y. J. Amer. Chem. Soc. 68, 914, 1946 report mp 346-347° C.].
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>O>[CH2:3]1[O:4][C:5]2([CH2:10][CH2:9][N:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:7][CH2:6]2)[O:1][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
1,4-Dioxa-8-azaspiro[4,5]decane (7.88 g) was dissolved in N-methyl-2-pyrrolidine (50 mL), and diisopropylethylamine (9.58 mL) and 4-fluoronitrobenzene (7.06 g) were successively added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was added to iced water, and the precipitated solid was collected by filtration to give N-(4-nitrophenyl)-4-piperidone ethylene ketal (10.6 g) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=C)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].I([O-])(=O)(=O)=[O:35].[Na+].C(OCC)(=O)C.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:35])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: C=CCn1cc(C(=O)NCc2ccc(F)cc2)c(=O)c(OCc2ccccc2)c1C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of the compound 15 (7.6 g, 16.9 mmol) in 1,4-dioxane (228 ml) was added an aqueous solution (8 ml) of potassium osmate dihydrate (372 mg, 1.01 mmol), and sodium metaperiodate (14.5 g, 67.6 mmol) was further added, followed by stirring at room temperature for 2 hours. The reaction solution was added to a vessel to which ethyl acetate (30 ml) and water (30 ml) had been added, while stirring. The organic layer was washed with water, a 5% aqueous sodium hydrogen sulfite solution and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-(2-oxo-ethyl)-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 16 (5.89 g, 71%) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:15][OH:16].C(N(CC)CC)C>CO>[NH2:13][C:12](=[N:15][OH:16])[C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH:11]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cncc(C#N)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Ethyl-(5-cyano-3-pyridyl)carboxylate) (WO 96/30372) (1.8 g, 10.2 mmol) was dissolved in methanol (50 mL), the solution was cooled to 0° C. then hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and triethylamine (1.4 mL, 10.2 mmol) were added and the mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (graded elution of dichloromethane/methanol 95:5 to 93:7) to give the title compound as a white solid which contained 0.3 equivalents of triethylamine hydrochloride (2.5 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:41]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-methylsulfonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (37%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])CCC.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>O1CCCC1.CCCCCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:5]1[S:4][C:3]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[C:2]([CH3:1])[CH:6]=1
Reactant: BrCCCCBr
Reactant: Cc1ccsc1C1OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCCCBr)sc1C1OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of 2-(3-methyl-2-thienyl)-1,3-dioxolane (12.3 g) in dry tetrahydrofuran (150 ml) was treated with a solution of n-butyl lithium in hexane (1.6M, 50 ml) at -60°, under nitrogen. After 1 h, 1,4-dibromobutane (17.3 g) was added and the mixture was stirred at -50° for 3 h and at room temperature for 18 h. Water (75 ml) was added and the mixture extracted with ether. The organic extract was distilled to give the title compound as a light brown oil (15.1 g) b.p. 250°/0.15 mm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](Cl)=O)[CH3:13]>O1CCOCC1.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]1[NH:1][C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[S:8](=[O:10])(=[O:9])[N:11]=1)[CH3:13]
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: CCOC(=O)CC(=O)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1=NS(=O)(=O)c2ncccc2N1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
3-Amino-pyridine-2-sulfonic acid amide (1.8 g, 10.4 mmol) was dissolved in 1,4-dioxane (45 mL). Chlorocarbonyl-acetic acid ethyl ester (1.57 mL, 12.48 mmol) was added. The mixture was stirred at 90° C. for 1.5 h. Upon cooling, the mixture was diluted with ethyl acetate (300 mL) and washed with half-saturated aqueous sodium bicarbonate solution (100 mL) followed by saturated aqueous brine solution (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oily residue was treated with toluene (36 mL) and triethylamine (9 mL). The mixture was stirred at 110° C. in a sealed tube for 1.5 h. The residue never completely dissolved. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. Trituration with a minimal amount of ethyl acetate (˜5 mL) solidified the product. The solids were collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid ethyl ester (0.3 g, 1.11 mmol, 11%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.21 (3H, t, J=7.0 Hz), 3.71 (2H, s), 4.16 (2H, quartet, J=7.1 Hz), 7.70-7.76 (2H, m), 8.62 (1H, dd, J1−4.0 Hz, J2=1.5 Hz), 12.29 (1H, bs). LC-MS (ESI) calcd for C10H11N3O4S 269.05, found 270.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10].[OH-].[Na+].[Na]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: Brc1ccc(Br)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cc(Br)ccc1Br
Temperature: 150 °C
Yield: 86 %

Procedure:
A modification of the published procedures of H. Borns, Annalen der Chemie 1877, 187, 350 was used. A 300 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 1,4-dibromobenzene (118 g, 0.50 moles) and 30% fuming sulfuric acid (76 mL). The mixture was heated to 150° C. for 3 hours under nitrogen to give a clear solution. The solution was cooled to room temperature to give a solidified mass and transferred into a beaker with water to give a slurry. The slurry was treated with 50% sodium hydroxide solution (130 g) and diluted to 900 mL with water with heating to disperse the precipitated solids. The mixture was cooled to room temperature and the solids collected by vacuum filtration under a rubber dam. The solids were washed with two times with isopropanol (200 mL) and air dried on the filter then dried under vacuum at 100° C. to give 159 g (93% crude yield). The product was recrystallized from ethanol/water (4:1) and dried under vacuum at 150° C. to give 146 g (86% yield) of 2,5-dibromobenzenesulfonic acid, sodium salt. 1H NMR (DMSO-d6): 7.42 (dd, 8.4, 2.6 Hz, 1H), 7.53 (d, 8.4 Hz, 1H), 8.01 (d, 2.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=O)[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.Cl.[CH2:35]([NH:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:35]([NH:42][NH:43][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)NNCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Yield: 41.6 %

Procedure:
A mixure of 3.46 g of (E)-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid, 4.0 g of N-methyl morpholine, 2.95 g of benzylhydrazine dihydrochloride and 1.7 g of 1-hydroxybenzotriazole hydrate in 25 ml of dimethylformamide was cooled to 0° C. while stirring under nitrogen and 2.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added. The mixture was gradually allowed to come to room temperature and was then stirred overnight. The dimethylformamide was evaporated and the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The ethyl acetate phase was washed in sequence with water, 5% citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the ethyl acetate was evaporated to give a yellow gum. Crystallization from hexane gave 1.87 g of (E)-2′-benzyl-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[S:19]1[CH:23]=[CH:22][N:21]2[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[N:26]=[C:20]4[N:21]([CH:24]=3)[CH:22]=[CH:23][S:19]4)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2ccsc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccsc2n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.31 g, 1.19 mmol), imidazo[2,1-b]thiazole-6-carboxylic acid (0.2 g, 1.19 mmol), HOBt (0.24 g, 1.78 mmol), DIPEA (0.62 mL, 3.57 mmol) and EDCI (0.34 g, 1.78 mmol) using DMF (10 mL) as solvent using the method of Example 34(d) affording 232 mg of the product. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 4.38 (m, 2H), 4.55 (m, 1H), 6.76 (d, 1H), 7.21 (d, 1H), 7.75 (m, 3H), 7.90 (dd, 1H), 8.06 (m, 1H), 8.09 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>C1COCC1.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11]2)=[N:17][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc(N)cn2)C1
Yield: 95 %

Procedure:
To a solution of tert-butyl methyl(1-(5-nitropyridin-2-yl)piperidin-3-yl)carbamate (1.03 g, 3.1 mmol) in THF (50 mL) was added Pd/C (10 wt. %, 500 mg). The reaction mixture was stirred under 1 atm of hydrogen for 16 h, filtered through celite and concentrated to afford the desired product (902 mg, 96%) as a red oil. ESI MS m/z 307 [C16H26N4O2+H]+