Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39]([C:40]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=O)=[CH:38][C:37]=2[O:36]1>O1CCCC1.O>[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39](/[C:40](/[C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:38][C:37]=2[O:36]1
Reactant: O=C(c1cccnc1)c1ccc2c(c1)OCO2
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C(\c1cccnc1)c1ccc2c(c1)OCO2
Temperature: 85 °C
Yield: 11.2 %

Procedure:
Sodium hydride (1 g, 60% in oil) was added to dimethyl sulfoxide (25 ml) under nitrogen and the mixture was heated at 85° C. with stirring for an hour. The reaction mixture was cooled to room temperature and 5-carboxypentyltriphenylphosphonium bromide (5.2 g, 11 mmoles) was added gradually. The mixture was stirred for 10 minutes and a solution of 3-(3,4-methylenedioxybenzoyl)pyridine (2.5 g, 0.11 mole) in tetrahydrofuran (10 ml) was added dropwise thereto. After completion of addition, the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, water (100 ml was added and the neutral substance was extracted twice with toluene (50 ml). The aqueous layer was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the eluent. The eluate was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (Z)-7-(3,4-methylenedioxyphenyl)-7-(3-pyridyl)-6-heptenoic acid (0.4 g, 24.6%). Mp 90°-91° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[O:15]=[C:16]([C@@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[CH2:17][CH2:18][C@H:19]1[NH:22][C:21](=[O:23])[C@H:20]1[NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCCl>[OH:3][CH:2]([N:22]1[C@H:19]([CH2:18][CH2:17][C:16](=[O:15])[C@@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[C@H:20]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]1=[O:23])[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C=O)cc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1CCC(=O)[C@@H]1CCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
p-Methoxybenzyl glyoxylate (3.20 g, 16.5 mmol) in 1,2-dichloroethane (50 ml) was heated at reflux for 1h. using Dean and Stark apparatus. The solution was cooled in ice and treated successively with (3S,4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phenylacetamidoazetidin-2-one (4.10 g, 12.4 mmol) and triethylamine (170 μl, 1.22 mmol). After stirring at 0° C. for 30 min., the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexane, then ethyl acetate to yield the title compound as a yellow foam (4.53 g, 70%); νmax (CH2Cl2) 3420, 3226, 1769, 1743, 1681, 1613 and 1516 cm-1 ; m/z (FAB, +ve ion, 3-nitrobenzyl alcohol/sodium acetate) 547 (MNa+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:15].[CH:16]1[C:21]([NH:22][NH2:23])=[CH:20][CH:19]=[C:18]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:17]=1.Cl>O>[O:15]=[C:2]1[C:3](=[N:23][NH:22][C:21]2[CH:20]=[CH:19][C:18]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:17][CH:16]=2)[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=2)[NH:1]1
Reactant: NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)cc1

Procedure:
The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid amide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 7.04 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.26 (s, 2H), 7.60 (d, J 8.9 Hz, 2H), 7.70 (dd, J=8.2, 1.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.98 (d, J=1.6 Hz, 1H), 11.43 (s, 1H), 12.75 (s, 1H); APCI−MS m/z 395 (M)−. Anal. Calcd for C14H13N5O5S2.0.5 H2O: C, 41.58; H, 3.49; N, 17.32; S, 15.86. Found: C, 41.67; H, 3.46; N, 17.26; S, 15.78.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Li+].[H-].C(O)(C)C.[CH2:17]([CH:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[CH:18]=[CH2:19]>CCCCCC.C(OCC)C>[CH2:17]([C@@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]1)[CH:18]=[CH2:19]
Reactant: C=CCC1CCCC(=O)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CC[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0° C. After the evolution of gas has ended, 12.4 g of 3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M hydrochloric acid and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N sodium hydroxide solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=15:1=>5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H16O (140.23), MS(ESI): 141 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.22.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([Mg]Cl)(C)C.[C:28]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:28]([OH:35])([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1nc2ccc(I)cc2c(Cl)c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccnc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)(c2cccnc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(Cl)c3c2)CC1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
To a solution of 4-chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline (Intermediate 20: step b, containing about 13% molar of 4-chloro-3-phenyl-2-(trifluoromethyl)quinoline as impurity, 340 mg) in THF (4 mL) at −78° C. under N2 was added iPrMgCl (2.0 M in THF, 0.40 mL, 0.8 mmol). After stirring for 8 minutes, the cooling bath was removed, and stirring was continued for 20 minutes, then tert-butyl 4-nicotinoylpiperidine-1-carboxylate (225 mg, 0.770 mmol, Intermediate 21) was added in neat. After stirring at room temperature overnight, the mixture became clear brown and was heated at 50° C. for 1.5 hours. The mixture was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography (silica gel, 20-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.17-9.35 (m, 1H), 8.50-8.88 (m, 2H), 8.29 (d, J=7.58 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 7.82-8.00 (m, 1H), 7.47-7.57 (m, 4H), 7.21-7.33 (m, 2H), 4.08-4.26 (m, 2H), 2.69-2.99 (m, 3H), 1.82-1.92 (m, 1H), 1.53-1.80 (m, 3H), 1.47 (s, 4.5H), 1.41 (s, 4.5H); MS m/e 598.3 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])[CH2:3][CH2:2]1.C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[CH3:43][C:44]1[S:45][C:46]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][C:47]=2[N:48]=1>>[OH:15][C:8]1([C:51]2[C:50]([OH:53])=[CH:49][C:47]3[N:48]=[C:44]([CH3:43])[S:45][C:46]=3[CH:52]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][CH2:4][CH2:1][CH2:3][CH3:2])[C:7]1=[O:16]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc3sc(C)nc3cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 2-methyl-1,3-benzothiazol-5-ol, the title compound was obtained (81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.90 (br, 1H), 9.05 (br, 1H), 7.78 (d, 1H), 7.25 (dd, 1H), 7.10-6.95 (m, 2H), 6.90-6.80 (m, 2H), 3.81-3.58 (m, 2H), 2.75 (br, 3H), 1.80-1.60 (m, 2H), 1.50-1.31 (m, 4H), 0.90 (t, 3H); MS (ES+) m/z 383.4 (M+1).
Reaction SMILES: Cl[C:2]1([CH2:7][C:8]([Cl:11])([Cl:10])Cl)[O:5][C:4](=[O:6])[CH2:3]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(OC)(C)C>[Cl:11][C:8]([Cl:10])=[CH:7][C:2](=[O:5])[CH2:3][C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: O=C1CC(Cl)(CC(Cl)(Cl)Cl)O1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C(C=C(Cl)Cl)CC(=O)N1CCOCC1
Temperature: 15 °C
Yield: 72927.5 %

Procedure:
Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N+]([O-])=O)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(Cl)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 4-chloro-2-nitropyridine (2.53 g, 16 mmol, 2 eq.) in 50 ml DMF was added cesium carbonate (7.8 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=19:1 to 4:1) to give desired product as light yellow oil. MS (ESI) m/z=721 [2M−H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Br)[N:5]=[C:4]([NH:11]C(=O)C)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].B(CC)(CC)[CH2:22][CH3:23]>CN(C=O)C.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]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:22][CH3:23])[N:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: CCB(CC)CC
Reactant: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCc1nc(N)cc(N)c1C#N
Reaction time: 0.33 h
Yield: 39.6 %

Procedure:
A mixture of 4,6-diamino-2-bromo-nicotinonitrile from Example 65A (250 mg, 1.2 mmol), Pd(dppf)Cl2 (96 mg, 0.12 mmol), Cs2CO3 (576 mg, 1.8 mmol) in anhydrous DMF was flushed with nitrogen for 5 min before BEt3 (1.0 M solution in hexane, 1.42 mL, 1.4 mmol) was added. The sealed tube was heated@ 120° C. in a microwave reactor for 20 min. The reaction mixture was then partitioned between EtOAc and water, the organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel sep-pak, eluting with 30-50% EtOAc in hexane. The product was further purified by recrystalization from EtOAc/hexane to provide the titled compound as a light brown solid (77 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6) δ 6.18 (s, 2H), 6.10 (s, 2H), 5.52 (s, 1H), 2.54 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H); MS (ESI) m/e 163 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]3([C:27]4[N:28]=[N:29][N:30]([CH:32]([F:34])[F:33])[N:31]=4)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.FC1C=CC=C(F)C=1COC1C2N(C(C(NC3(C4N(C(F)F)N=NN=4)COC(C)(C)OC3)=O)=C(C)N=2)C=CC=1.Cl.C(OC(C)C)(C)C>C(OCC)(=O)C.CO>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:27]3[N:28]=[N:29][N:30]([CH:32]([F:34])[F:33])[N:31]=3)([CH2:20][OH:21])[CH2:24][OH:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2nnn(C(F)F)n2)COC(C)(C)OC1
Agent: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2nnnn2C(F)F)COC(C)(C)OC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)(CO)c1nnn(C(F)F)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
23.6 g of a mixture of 8-[(2,6-difluorobenzyl)oxy]-N-{5-[2-(difluoromethyl)-2H-tetrazol-5-yl]-2,2-dimethyl-1,3-dioxan-5-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide and 8-[(2,6-difluorobenzyl)oxy]-N-{5-[1-(difluoromethyl)-1H-tetrazol-5-yl]-2,2-dimethyl-1,3-dioxan-5-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide, a mixture of 220 ml of methanol and 220 ml of 1 M hydrochloric acid was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform/methanol=9:1. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 15.1 g of a crude product. To this crude product were added 30 ml of ethyl acetate and 150 ml of diisopropyl ether, followed by stirring at room temperature for 1 hour. The insoluble materials were separated by filtration, and the solid was washed with 100 ml of diisopropyl ether and dried under reduced pressure to obtain 12.9 g of 8-[(2,6-difluorobenzyl)oxy]-N-{2-[2-(difluoromethyl)-2H-tetrazol-5-yl]-1,3-dihydroxypropan-2-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: COCCOC[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([S:19]([NH2:22])(=[O:21])=[O:20])[S:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16].S(=O)(=O)(O)O>CO>[OH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([S:19]([NH2:22])(=[O:20])=[O:21])[S:13][C:14]=1[S:15]([CH3:18])(=[O:16])=[O:17]
Reactant: COCCOCOCCc1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CS(=O)(=O)c1sc(S(N)(=O)=O)cc1CCO
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
The 4-[2-(methoxyethoxymethoxy)ethyl]-5-methylsulfonylthiophene-2-sulfonamide (6.6 g, 0.0177 mol) was dissolved in methanol (25 ml) and was stirred at room temperature as cold 50% (v/v) sulfuric acid (40 ml) was added dropwise over 10 minutes. An additional quantity of methanol (25 ml) was added to dissolve the gum which separated and the solution was stirred for 1/2 hour. The solution was basified with sodium hydroxide and was washed with ether. The solution was acidified with HCl and was extracted with CHCl3 and then with ethyl acetate. The ethyl acetate extract was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature to give 4.1 g of crude oil which was chromatographed on silica gel (100 g) eluting with 5% methanol in chloroform. There was recovered 2.5 g of white solid which provided 1.5 g of analytically pure, material, m.p. 120-124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2o1)c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2nc(NC(=O)c3ccccc3)oc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of N-(6-nitrobenzoxazol-2-yl)benzamide (2.03 g, 7.17 mmol) in dimethylformamide (60 mL), palladium on charcoal (1.52 g, 10% Pd, 1.43 mmol Pd) was added and the air was replaced with hydrogen (1 bar). The mixture was stirred for 2 h at 60° C. and then overnight at r.t. The palladium was removed by filtration through a pad of celite. After concentration to 20 mL, water was added and the resulting precipitate was separated by filtration to obtain N-(6-aminobenzoxazol-2-yl)benzamide (0.823 g, 3.25 mmol, 45%) as a brown solid. LC/ESI-MS: m/z=254 [M+H]+; m/z=252 [M−H]−; Rt=1.92 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:34]=[C:29]([CH2:30][CH2:31][O:32][CH3:33])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: COCCC(N)=NO
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 59A and 30 mg (0.25 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 32 mg (44% of theory)
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.Cl.N1CCOCC1.O1CCOCC1.[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]=[O:25]>C(OC)(C)(C)C.O>[OH:25][CH:24]1[O:6][C:2](=[O:5])[CH:3]=[C:23]1[CH2:22][C:21]([F:27])([F:26])[F:20]
Reactant: O=CC(=O)O
Reactant: O=CCCC(F)(F)F
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCN1
Product: O=C1C=C(CC(F)(F)F)C(O)O1
Yield: 81 %

Procedure:
Glyoxylic acid monohydrate (2.43 g, 26.4 mmol), morpholine hydrochloride (3.59 g, 29 mmol) and dioxane (10.5 ml) are stirred together at room temperature. Water (14 ml) is added and the reaction mixture is stirred for a few minutes until it becomes homogeneous. 4,4,4-trifluorobutyraldehyde x99 (3.16 g, 25.1 mmol) is added and the mixture is stirred for 1 h at room temperature and under reflux conditions overnight. The mixture is diluted in tert-butylmethylether and washed with water. The aqueous phase is re-extracted with tert-butylmethylether. The organic extracts are combined, dried over magnesium sulphate, filtered and concentrated in vacuo to obtain 5-hydroxy-4-(2,2,2-trifluoroethyl)furan-2(5H)-one x100 as a yellow oil (3.76 g, 81%). The product is used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH:21]([NH2:23])[CH3:22]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:23][CH:21]([CH3:22])[CH2:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(N)CN
Solvent: CCO
Product: CC1CN=C(c2ccc(F)cc2)C(c2ccc(F)cc2)=N1
Yield: 86 %

Procedure:
First, with ethanol as a solvent, 5.31 g of 4,4′-difluorobenzil (by Tokyo Chemical Industry Co., Ltd.) and 1.60 g of 1,2-diaminopropane (by Kanto Chemical Co., Inc.) are mixed. Subsequently, the mixed solution is refluxed for three hours. Then, after the refluxed solution is condensed by using an evaporator and treated with ethanol and then recrystallized, 2,3-bis(4-fluorophenyl)-5-methyl-5,6-dihydropyrazine is obtained (light yellow powder, yield: 86%).
Reaction SMILES: C([N:8]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:24]1[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:9][NH:8][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C=C(c1ccccn1)O2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccn1)O2
Temperature: 70 °C
Yield: 99.4 %

Procedure:
To tert-butyl 8-benzyl-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undec-9-ene-3-carboxylate (80 mg, 0.19 mmol) in methanol (13 mL) was added Pd(OH)2 (50 mg, 0.36 mmol) and ammonium formate (180 mg, 2.85 mmol) and the reaction mixture was heated at 70° C. for 1 hour. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite®. The organic layer was washed with 1:1 NaOH:NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to yield tert-butyl 10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (63 mg, 100%) as an oil which was used in the next step without further purification. ESI-MS m/z calc. 333.4. Found 334.4 (M+1)+; Retention time: 1.00 minutes (3 min run).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:14]2[CH:26]=[CH:27][O:28][C:13]=2[CH2:12]1)=O)(C)(C)C.[ClH:29].C(OCC)(=O)C>CO>[ClH:24].[ClH:29].[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:14]2[CH:26]=[CH:27][O:28][C:13]=2[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(2-[(tert-Butoxycarbonyl)amino]ethyl)-4-(3,4-di-chlorophenyloxy)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine (35 mg) prepared in the step 1 was dissolved in 2 mL of dehydrated methanol, 20 equivalents of a hydrochloric acid/ethyl acetate solution was dropped thereinto and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to evaporate the solvent and excess hydrochloric acid. To the resulting residue was added 2 mL of diethyl ether, the mixture was stirred and the solid separated out therefrom was filtered and dried to give 8 mg of the objective compound.