Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[N:16]=[N+:17]=[N-:18])=[CH:13][CH:12]=[C:11]([Cl:19])[CH:10]=2)=[O:5])C>[OH-].[Na+]>[N:16]([C:15]1[C:14]2[C:9](=[CH:10][C:11]([Cl:19])=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])=[N+:17]=[N-:18]
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: [N-]=[N+]=Nc1c(C(=O)O)cnc2cc(Cl)ccc12

Procedure:
Ethyl-4-azido-7-chloroquinoline-3-carboxylate (0.57 g; 0.002 M) in 10% aq. NaOH (10 ml) and stirred at 40° C. for 5 hr. The unreacted ester, m.p. 91°-4° C., was filtered off, the filtrate acidified to pH 3 with 5 M HCl, the product filtered off, washed well with water and dried in vacuo over P2O5. 0.33 g (66%), m.p. 284°-6° C. (dec.), (Found: C, 46.7; H, 2.3; Cl 14.1%. C10H5ClN4O2.1/2H2O requires C, 46.6; H, 2.4; Cl 13.8%), νmax (KBr) 2158, 1705 (br), 1608, 1562, 1395 (br), 1210 and 798 cm-1, δ [(CD3)2SO] 7.72 (m), 8.09 (d), 8.36 (d) and 9.18 (s) (aromatic H's)
Reaction SMILES: ClNCl.[ClH:4].[CH3:5][CH:6]([CH2:18][CH3:19])[CH2:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:5][CH:6]([CH2:18][CH3:19])[CH2:7][O:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([Cl:4])[CH:15]=1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: Cl
Agent: ClNCl
Solvent: CC(=O)O
Product: CCC(C)COC(=O)c1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
On the other hand, dichloroamine T (28.0 g, 0.12 mol) was dissolved in acetic acid (450 ml), and hydrochloric acid (1.5 ml) was added. The resulting solution was dropwise added to a solution of the above p-hydroxybenzoic acid 2-methyl-butyl ester (50 g, 0.24 mol) dissolved in acetic acid (450 ml), followed by refluxing the mixture, allowing to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3-chloro-4-hydroxy-benzoic acid 2-methyl-butyl ester (42 g) (b.p. 135°~138° C./4 mmHg).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6]1)C.Cl.[NH2:14][C:15](=[NH:29])[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.C[O-].[Na+]>CO>[CH3:12][N:7]1[CH2:8][CH2:9][C:10]2[N:29]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]3)[N:14]=[CH:4][C:5]=2[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=N)N)C1
Reactant: CN(C)C=C1CN(C)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ncc2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
3-[(Dimethylamino)methylene]-1-methylpiperidin-4-one (9.04 g, 53.7 mmol) and tert-butyl {(3R)-1-[amino(imino)methyl]pyrrolidin-3-yl}carbamate hydrochloride (14.2 g, 53.7 mmol) were dissolved in methanol (100 mL) and to this was added dropwise sodium methoxide (9.66 g of a 30% solution in methanol). The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was then evaporated to dryness, and the residue was treated with water (50 mL). The precipitate was separated by filtration, washed with water (25 mL) and diethyl ether (50 mL) and dried to give the title compound 10.43 g (yield 58%). LCMS (ES+) M+H 334. 1H NMR (DMSO-d6) 1.39 (s, 9H) 1.85 (m, 1H) 2.13 (m, 1H) 2.33 (s, 3H) 2.60 (m, 2H) 2.67 (m, 2H) 3.23-3.26 (m, 1H) 3.31-3.37 (m, 3H) 3.40-3.536 (m, 1H) 3.63 (m, 1H) 4.04 (br s, 1H) 7.20 (br s, 1H) 8.04 (s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.O=P(Cl)(Cl)Cl.[C:20](=O)([O-])[O-:21].[K+].[K+]>CCO>[OH:13][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)[CH:12]=[CH:11][C:10]=1[CH:20]=[O:21]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: O=Cc1ccc(N2CCNCC2)cc1O
Temperature: 5 °C

Procedure:
890 mg (5 mmol) 3-Piperazin-1-yl-phenol are suspended in 100 mL EtOH and treated with 0.42 mL (1 eq.) 12N HCl at a temperature below 10° C. The suspension is stirred an hour and slowly evaporated. The remaining beige powder is dried under high vacuum, then taken up in 60 mL DMF. The solution is cooled to 5° C. under argon, 0.503 mL (1.1 eq.) POCl3 added dropwise and the reaction mixture stirred for an hour at room temperature, then 30 minutes at 80° C., and finally allowed to cool to room temperature, upon which 2 g (3 eq.) solid potassium carbonate is added. The suspension is stirred 30 minutes at room temperature then evaporated, and the residue resuspended and stirred in a 1:1 mixture of dichloromethane and isopropanol. The suspension is filtered, the filtrate evaporated and dried to yield 600 mg crude 2-hydroxy4-piperazin-1-yl-benzaldehyde. This material is taken up in 40 mL of a 1:1 mixture of benzene and acetonitrile, 2.5 mL (5 eq.) piperidine and 683 mg (0.66 eq.) benzothiazol-2-yl-acetic acid methyl ester are added under argon and the reaction mixture refluxed for an hour. The product is extracted with dichloromethane and brine at 0° C., the combined organic phases dried with sodium sulphate, filtered and evaporated, then triturated with diisopropylether to yield 800 mg desired product (crude).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:9])[C:6]=1[CH:7]=[O:8]
Reactant: Cc1c(CO)c(C)n(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cc1c(C=O)c(C)n(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 70.7 %

Procedure:
Using [2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (0.84 g), tetra-n-propylammonium perruthenate (57.3 mg), N-methylmorpholine N-oxide (437 mg) and molecular sieves 4A powder (422 mg), a procedure as in Reference Example 6 was performed to give the title compound as a brown oil (yield 0.59 g, 71%).
Reaction SMILES: Br/[CH:2]=[C:3](/[C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([Cl:22])=[CH:16][CH:15]=1)\[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:10]([C:7]1[CH:8]=[CH:9][C:4](/[C:3](/[C:14]2[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([O:20][CH3:21])[N:19]=2)=[CH:2]\[N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:5][CH:6]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1nc(/C(=C/Br)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(/C(=C/N2CCCC2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 130 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A solution of 6-[(E)-2-bromo-1-(4-tert-butylphenyl)ethenyl]-3-chloro-2-methoxypyridine obtained in Reference Example 4-7 (109 mg), 2-pyrrolidone (73 mg), tris(dibenzylideneacetone)dipalladium(0) (11 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (22 mg) and cesium carbonate (329 mg) in toluene (3 mL) was stirred at an external temperature of 130° C. for four hours in a nitrogen atmosphere. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to give 1-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a yellow powder (82 mg, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=O.C1C=CC=CC=1>O>[CH:8]([C:6]1([CH3:5])[NH:1][CH2:2][CH2:3][S:4]1)([CH3:10])[CH3:9]
Reactant: CC(=O)C(C)C
Reactant: NCCS
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1(C)NCCS1
Yield: 77.5 %

Procedure:
15.43 g (0.2 mol) of cysteamine and 29.0 g (0.2 mol) of isopropyl methyl ketone were treated with 200 ml of benzene and boiled under an inert gas atmosphere for 14 hours on a water-separator. The solution was concentrated on a rotary evaporator and filtered over 25 g of neutral aluminium oxide (activity I). The aluminium oxide was then flushed with ether. The filtrate was again concentrated and subsequently distilled under a high vacuum through a Widmer column. 22.51 g (yield 77% of theory) of 2-isopropyl-2-methyl-thiazolidine (nD20 = 1.5085) passed over in a boiling range of 40°-42° C and at a pressure of 0.009 mm Hg. IR: νmax = 1440, 1370, 790 cm-1. Odour: camphorous, woody; flavour: greenish.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH2:36][C:37]3[CH:45]=[C:44]([CH3:46])[C:43]4[C:39](=[CH:40][N:41](COCC[Si](C)(C)C)[N:42]=4)[CH:38]=3)[C:22](=[O:35])[N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][CH:21]([CH2:36][C:37]3[CH:38]=[C:39]4[C:43](=[C:44]([CH3:46])[CH:45]=3)[NH:42][N:41]=[CH:40]4)[C:22](=[O:35])[N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[CH2:27][CH2:28]3)=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(CC(OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-3-(7-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (112 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 2 h. The reaction was concentrated and purified by column chromatography (5% methanol/dichloromethane to 7:93:1 methanol/dichloromethane/33% trimethylamine in ethanol) gave 89.6 mg (97%) as a white solid. Mass spec.: 755.37 (MH)+.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34](C(OC(C)(C)C)=O)[CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[CH:23]=2)=[N:20][C:19]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH:57]([CH3:59])[CH3:58])(=[O:56])=[O:55])=[CH:50][CH:49]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.CCO>[CH:57]([S:54]([C:51]1[CH:52]=[CH:53][C:48]([C:19]2[N:20]=[C:21]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)=[CH:29][CH:28]=4)[CH:23]=3)[C:16]([NH2:8])=[N:17][CH:18]=2)=[CH:49][CH:50]=1)(=[O:56])=[O:55])([CH3:59])[CH3:58]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CN(C(=O)OC(C)(C)C)C5CCOCC5)cc4)no3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc(CNC5CCOCC5)cc4)no3)n2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A suspension of tert-butyl tert-butoxycarbonyl(3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate (A-6) (410 g; 492 mmol) in CH2Cl2 (410 mL) is stirred at ambient temperature in a flask. TFA (841 g, 568 mL; 7.4 mol) is added while maintaining the reaction temperature between 20-25° C. The solution is stirred at ambient temperature for about 3 h when analysis shows reaction completion. The solution is cooled to about 5-10° C. and diluted with EtOH (3.3 L) while maintaining the temperature below 20° C. A 5.0 M aqueous solution of NaOH (1.77 L; 8.85 mol) is added while allowing the reaction temperature to rise from about 14° C. to about 42° C. The suspension is heated at 70-75° C. for 6 h while removing distillate. The suspension is allowed to cool to ambient temperature. The solid is collected by filtration and the filter-cake is washed with water (4×1.64 L). The filter-cake is washed with EtOH (2×820 mL) and dried to afford 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl) isoxazol-5-yl)pyrazin-2-amine (Compound I-1) (257 g; 98% yield, 99.5 area % purity by HPLC) as a yellow powder. 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.44-8.33 (m, 2H), 7.94 (t, J=8.2 Hz, 4H), 7.76 (s, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.20 (s, 2H), 3.83 (m, 1H), 3.80 (s, 3H), 3.46 (hept, J=6.8 Hz, 1H), 3.25 (td, J=11.4, 2.1 Hz, 2H), 2.66-2.54 (m, 1H), 1.79 (br dd, 2H), 1.36-1.22 (m, 2H), 1.19 (d, J=6.8 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 167.57, 151.76, 141.07, 137.58, 135.75, 129.16, 128.53, 126.57, 126.41, 125.69, 124.52, 102.13, 65.83, 54.22, 52.60, 49.19, 33.18, 15.20.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][CH3:18])[CH3:14].N1CCCCC1>CN(C=O)C.CCOC(C)=O.[Cu](I)I>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]1[O:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[CH:18]=1)[CH3:14]
Reactant: CCOC(CC)OCC
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: I[Cu]I
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1cc2ccc(C(=O)OC)cc2o1
Temperature: 45 °C
Reaction time: 6 h
Yield: 32.2 %

Procedure:
A dried flask under nitrogen is charged with methyl 3-hydroxy-4-iodobenzoate (10.0 g, 35.9 mmol), propioaldehyde diethyl acetal (5.72 ml, 40.0 mmol), bistriphenylphosphine palladium diacetate (538 mg, 0.72 mmol), copper iodide (273 mg, 1.4 mmol) and piperidine (3.94 ml, 40.0 mmol) in DMF (50 ml). The mixture is stirred at 45° C. for 6 h, then at RT overnight. The reaction is diluted with EtOAc (250 ml) and washed with 50% saturated 1:1 NaCl/NaHCO3 solution (4×100 ml). The organic layer is dried (Na2SO4), filtered and concentrated to a brown oil. The crude material is chromatographed over 500 g slurry-packed silica, eluting with 15% EtOAc/hexane. The appropriate fractions are collected and concentrated, affording 3.22 g (32%) of methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate as an orange oil. 1H NMR (400 MHz, CDCl3): δ 1.29, 3.72, 3.96, 5.70, 6.88, 7.61, 7.95, 8.20 ppm.
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]23[O:22][CH2:21][C:18]([CH2:23][CH2:24][CH3:25])([CH2:19][O:20]2)[CH2:17][O:16]3)[CH2:11][CH2:10]1.CCOCC>CCCCCC.O1CCCC1>[C:8]([CH:9]1[CH2:10][CH2:11][CH:12]([C:15]23[O:16][CH2:17][C:18]([CH2:23][CH2:24][CH3:25])([CH2:19][O:20]2)[CH2:21][O:22]3)[CH2:13][CH2:14]1)#[CH:7]
Reactant: CCCC12COC(C3CCC(C=C(Br)Br)CC3)(OC1)OC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC1CCC(C23OCC(CCC)(CO2)CO3)CC1

Procedure:
n-Butyllithium (1.6 ml of a 1.1M solution in hexane) was added at -70° C. to a solution of 1-[4-(2,2-dibromovinyl)cyclohexyl]-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane (0.25 g) in dry tetrahydrofuran (5 ml) under a stream of nitrogen. After warming to room temperature over 2 hours ether (~25 ml) was added. The ethereal solution was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography on alumina eluting with 3:7 dichloromethane:hexane saturated with ammonia. 1-(4-Ethynylcyclohexyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a colourless oil (0.13 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl.[Cl:11][CH2:12][C:13](=[NH:16])OC>CO>[ClH:11].[CH3:1][O:2][N:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:13](=[NH:16])[CH2:12][Cl:11])[CH2:6][CH2:5]1
Reactant: COC(=N)CCl
Reactant: CON=C1CCNCC1
Agent: Cl
Solvent: CO
Product: CON=C1CCN(C(=N)CCl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.5 %

Procedure:
2 ml of a methanolic solution containing 1.064 g of 4-methoxyiminopiperidine was added to a solution of 1.195 g of methyl 2-chloroacetimidate hydrochloride in 4 ml of absolute methanol, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the concentrate was mixed with anhydrous ether. The crystals which separated out were collected by filtration and washed with ether, giving 1.5 g of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH3:12][S:13]([O:16][C@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])[C@H:19]([C:35]([N:37]2[CH2:41][CH2:40][NH:39][C:38]2=[O:42])=O)[CH2:18]1)(=[O:15])=[O:14].CO>O1CCCC1.C(OCC)(=O)C>[CH3:12][S:13]([O:16][C@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])[C@H:19]([CH2:35][N:37]2[CH2:41][CH2:40][NH:39][C:38]2=[O:42])[CH2:18]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
To a solution of sodium borohydride (0.32 g) in tetrahydrofuran (20 ml) was added dropwise boron trifluoride etherate (6.0 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-1(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (2.0 g) in tetrahydrofuran (10 ml) and the mixture was stirred at ambient temperature for 3 hours. To a reaction mixture was added dropwise methanol (30 ml) under ice-cooling and the solution was evaporated in vacuo. The resulting residue was dissolved in methanol (30 ml) and concentrated hydrochloric acid (0.5 ml) and stirred overnight at ambient temperature. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of ethyl acetate (60 ml) and tetrahydrofuran (30 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.81 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14](=[O:28])[C@:15]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)([OH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1>[NH:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14](=[O:28])[C@:15]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)([OH:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1.[ClH:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy)pyrrolidine-1-carboxylic acid t-butyl ester (1.3 g) in 8 ml 1,4-dioxane was added to 4 ml of 4M HCl in 1,4-dioxane and stirred at room temperature overnight to yield the title compound as an HCl salt (1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: CNCC(=O)O
Solvent: Cc1ccc(C)cc1
Product: CN1CC(=O)Nc2cccc(Cl)c2C1=O
Temperature: 25 °C

Procedure:
25.0 g 6-chloro-isatoic anhydride (II) and 12.4 g sarcosine were suspended under stirring and argon atmosphere in 100 ml p-xylene and heated at reflux for two hours. The suspension was cooled to room temperature and further stirred 1 hour, then filtered off. The precipitate was washed with 25 ml p-xylene twice and dried at 50° C. under vacuum. The solid so obtained (6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (III)) was digested in 75 ml deionized water at 0° C. for 1 hour, filtered off, washed with 25 ml deionized water and dried under vacuum 18 hours at 80° C. Crude product: 25.2 g as a beige powder. m.p. 230-232° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C(OCC)(=O)C.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[N:11]=2)[CH3:13])=[CH:15][CH:16]=1
Reactant: Cc1nc(N(C)c2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Yield: 77.9 %

Procedure:
A mixture of (2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methylamine (200 mg, 0.68 mmol) in 25 mL of ethyl acetate was hydrogenated over Palladium on carbon (70 mg) at 50 psi for 4 h, and the reaction mixture was filtered through a pad of celite and concentrated. The resulting crude product was purified by chromatography (50% ethyl acetate/hexane) to obtain the title compound (140 mg, 78%). 1H NMR (CDCl3): 7.71 (m, 1H), 7.51 (ddd, J=8.4, 6.9, 1.5, 1H), 7.09 (m, 1H), 6.93-7.05 (m, 3H), 6.68 (m, 2H), 3.74 (s, broad, 2H), 3.56 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].CS(Cl)(=O)=O.CCN(C(C)C)C(C)C.[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[C:27]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[N:28]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[N:29]=[C:23]2[NH:22][C:21]1=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+].S([O-])(=O)(=O)C>C(Cl)Cl>[CH2:3]([N:22]1[C:23]2=[N:29][N:28]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[C:27]([C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)=[C:24]2[C:25](=[O:26])[N:20]([CH3:19])[C:21]1=[O:47])[CH:2]=[CH2:1]
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Reactant: C=CCO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Allyl alcohol (17.7 μL, 0.261 mmol) was dissolved in anh. CH2Cl2 (1 mL) and cooled to −5° C. To this was added methanesulfonyl chloride (20.2 ul, 0.261 mmol) followed by N,N′diisopropylethylamine (45.4 μl, 0.261 mmol). The mixture was stirred at low temperature for 2 h. Meanwhile, 5-methyl-2-(1-naphthylmethyl)-3-(4-pyridinyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (100 mg, 0.261 mmol) was suspended in anh. N,N′dimethylacetamide (2 mL) followed by addition of cesium carbonate (85 mg, 0.261 mmol). at room temperature for 1 h. To the mixture was added the preformed mesylate and the mixture was heated at 100 ° C. for 4 h. Reaction was partitioned between ethylacetate and water. The organic phase was washed with water, brine and dried over sodium sulfate and concentrated in vacuo. The crude product was purified by semi prep HPLC eluting with acetonitrile/water/TFA mixtures.