Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:9][C@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].[Si:25]([O:32][C@@H:33]([C@H:35]1[C:62](=[O:63])[N:37]2[C:38]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:39](S(C3C=CC=CC=3)=O)[CH2:40][C@@H:36]12)[CH3:34])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][C@@H:33]([C@H:35]1[C:62](=[O:63])[N:37]2[C:38]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:39]([S:10][C@H:8]3[CH2:9][C@@H:5]([C:3](=[O:4])[N:2]([CH3:24])[CH3:1])[N:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])[CH2:7]3)[CH2:40][C@@H:36]12)[CH3:34])([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)C[C@@H]12
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@@H]12
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 18, but using (2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine and the crude 4-nitrobenzyl (5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 47, but used before purification by column chromatography) as starting materials, in relative proportions similar those used in that Example, the title compound was obtained as a foam-like solid in a yield of 89%.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[CH3:31])[CH2:20][CH2:19]1)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[CH2:32](Br)[CH:33]=[CH2:34].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].C(OC(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:34]([O:3][CH:4]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[CH3:31])[CH2:20][CH2:19]1)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: Cc1ccc(N2CCN(CC(O)CN3C(=O)c4ccccc4C3=O)CC2)c(C)c1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: C=CCOC(CN1CCN(c2ccc(C)cc2C)CC1)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
55% Sodium hydride (0.65 g) was suspended in anhydrous dioxane (30 ml), followed by dropwise addition of N-[2-hydroxy-3-{4-(2,4-dimethylphenyl)piperazin-1-yl}propyl]-phthalimide (4.7 g) dissolved in dioxane (50 ml) under nitrogen gas stream and at room temperature. The resulting mixture was heated to 60° C. and stirred for 1 hour. Then, allyl bromide (1.8 g) was dropped slowly into the mixture at 40° C. and the thus formed mixture was stirred for 3 hours over a water bath at 75° C. The reaction mixture was thereafter cooled, ice water was added thereto, and it was then extracted with ether. After washing the extract twice with water, it was dried with anhydrous magnesium sulfate. The resulting mixture was filtered and the filtrate was concentrated. After washing out the mineral oil, derived from sodium hydride, with n-hexane, the residue was dissolved in ethyl acetate, followed by addition of a solution which had been obtained by dissolving oxalic acid (1.2 g) in ethyl acetate. After heating the resulting mixture, a small amount of IPE (isopropyl ether) was added. The thus obtained mixture was allowed to cool. Precipitated crystals were collected by filtration to obtain the desired compound (4.3 g; yield 69%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH:16]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17]1.[CH:23]([O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:25])[CH3:24]>>[CH:16]1([S:19]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:31]([C:30]4[CH:29]=[CH:28][C:27]([O:26][CH:23]([CH3:25])[CH3:24])=[CH:33][CH:32]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)C4CC4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 393.18 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), cyclopropanesulfonyl chloride, 4-isopropoxy-aniline.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:50])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:39])=[O:50])=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)Oc1ccc(Oc2ccccc2)cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)N1CCC(O)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.4 %

Procedure:
A solution of 4-hydroxypiperidine (2.21 g, 21.8 mmol) and triethylamine (17.5 mL, 91 mmol) in 100 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 3 (9.0 g, 18.2 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 13.16 g of a yellow oil. Purification of the oil on silica gel (230-400 mesh) using hexane-ethyl acetate as the eluent gave 5.87 g (71%) of the title compound as a white waxy solid, mp 48°-55° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25](OCC)=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30]C)[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.ClC1C2C(=CC=C(CC)C=2)[N:37]=C(N2CC3C=CC=CC=3S(=O)(=O)CC2)C=1.C(#N)C=C>>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]#[N:37])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Reactant: CCc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Solvent: C=CC#N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC#N)c2c1

Procedure:
The title compound was prepared in analogy to ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoate in Example 95 in Scheme 46 by using 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and acrylonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)Cl.[OH-].[Na+].[NH4+:20].[OH-]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:20])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 0 °C
Yield: 87 %

Procedure:
A mixture of 5-methyl-2-nitrobenzoic acid (12) (36.2 g, 0.2 mol) and SOCl2 (50 mL) was heated under reflux for 20 min, during which a homogeneous solution was obtained. After removal of the excess SOCl2 with the aid of a water aspirator, the residue was dissolved in dry THF (40 mL) and the solution added dropwise with stirring to an ice-cold solution of NaOH (8 g, 0.2 mol) in 28% NH4OH (300 mL). The precipitate was collected, washed with water, and recrystallized from EtOH-H2O to obtain 5-methyl-2-nitrobenzamide (13) (31.5 g, 87%) as a white solid; mp 176°-177° C. [lit. (Findeklee, Ber. 38:3558, 1905) mp 176°-177° C.]; IR (KBr) V 1655 Cm-1 (amide C=O). A solution of 13 (31.5 g, 0.175 mol) in MeOH (250 mL) was shaken With 5% Pd-C (0.5 g) under 3 atm. of H2 for 24 h in a Parr apparatus. A solid formed after the initial heat of reaction subsided. The mixture was heated to boiling to redissolve the product, and was filtered while hot. The filtrate was evaporated under reduced pressure and the residue dried at 90° C. for 1 h (caution: some sublimation may occur) to obtain 2-amino-5-methylbenzamide (14) as a white solid (25.3 g, 96%); mp 173°-175° C. [lit. (Findeklee) mp 179° C.]; 1H-NMR (CDCl3) δ6.60 (d, 1H, J=8 Hz, C3 -H). To an ice-cold suspension of 14 (25.3 g, 0.168 mol) in 3.6N HCl (260 mL) was added dropwise over 25 min a solution of NaNO2 (12.75 g) in H2O (100 mL) while keeping the internal temperature below 5° C. After another 20 min of stirring at this temperature, 10N NaOH (100 mL) was added, causing all the solid to dissolve. The solution was acidified to pH 2 with 12N HCl and chilled. The solid was filtered and recrystallized from EtOH to obtain off-white needles (26.2 g, 97%); mp 217°-218° C. (dec, gas evolution) [lit. (Ferrand et al., Eur. J. Med. Chem. 2:337, 1987) mp 219°-220° C.]; IR (KBr) v 1680 (lactam C=O); 1H--NMR (d6 --DMSO+D2O) δ3.30 (s, 3H, 6--Me), 8.00 (m, 3H, aryl); UV (95% EtOH) λmax 208, 225, 282 nm.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:20])[CH3:19]>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:20][CH2:18][CH3:19])=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: CCS
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCSc1cc(N)cn[n+]1C

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 250 parts of acetonitrile is stirred with 10 parts of ethylmercaptan and 10 parts of triethylamine for four hours at 50° to 60° C. After the solvent has been distilled off the residue is washed with 100 parts of water. 18.3 parts (67.9% of theory) of 1-methyl-4-amino-6-ethylmercaptopyridazinium perchlorate is obtained; C7H12O4N3SCl, melting point 136° to 137° C after having been recrystallized from alcohol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:14][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:14][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5]2)=[N:1]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(cnn2C)c1
Product: COC(=O)c1ccc2nn(C)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.4 %
Yield: 40 %

Procedure:
To a solution of methyl 1H-indazole-5-carboxylate (2.5 g, 14 mmol) in DMF (45 mL) was added K2CO3 (4.90 g, 35.5 mmol) followed by iodomethane (1.77 mL, 28.4 mmol). The mixture was stirred at room temperature for 2 hours and then heated at 50° C. overnight. The mixture was concentrated, dissolved in EtOAc and washed with saturated aqueous NaCl. The organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 25-45% EtOAc/heptane) to provide methyl 1-methyl-1H-indazole-5-carboxylate (1.07 g, 40%) and methyl 2-methyl-2H-indazole-5-carboxylate (227 mg, 8.4%).
Reaction SMILES: [Br-].Cl[C:3]1[C:8]2=[C:9]([CH2:12][N+:13]([CH2:18][CH3:19])([CH2:16][CH3:17])CC)[CH:10]=[CH:11][N:7]2[N:6]=[CH:5][N:4]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1.[C:29]([O:33][C:34](=[O:42])[NH:35][CH:36]1CCNCC1)([CH3:32])([CH3:31])[CH3:30].FC(F)(F)C(O)=O>C(#N)C.CO>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:3]2[C:8]3=[C:9]([CH2:12][N:13]4[CH2:16][CH2:17][CH:36]([NH:35][C:34](=[O:42])[O:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:18]4)[CH:10]=[CH:11][N:7]3[N:6]=[CH:5][N:4]=2)[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC[N+](CC)(CC)Cc1ccn2ncnc(Cl)c12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Br-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(O)c(Cl)c4)c23)CC1
Yield: 73.4 %

Procedure:
Compound 21A (2.5 g) was prepared from 1E (2.5 g, 7.2 mmol), 4-amino-2-chlorophenol (1.03 g, 7.2 mmol) and piperidine-4-yl-carbamic acid tert-butyl ester (1.44 g, 7.2 mmol) in acetonitrile by a route analogous to that used in Method Two for the preparation of 1F. Analytical HPLC retention time=2.436 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=473+.
Reaction SMILES: NC1N=C2[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][N:5]2C(=O)C=1N=O.C(OC)(=[O:22])C(C)C.C(N)CN>>[C:14]([NH:13][CH2:12][CH2:11][NH2:5])(=[O:22])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CN1CCn2c1nc(N)c(N=O)c2=O
Reactant: COC(=O)C(C)C
Solvent: NCCN
Product: CC(C)C(=O)NCCN

Procedure:
7-AMINO-2,3-DIHYDRO-1-(2-METHYLPROPYL)-6-NITROSOIMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONE. Methyl isobutyrate and ethylenediamine in a molar ratio of 1:3 were heated in a closed pressure vessel at 100° for 62 hrs. The mixture was cooled, clarified by filtration, and the excess ethylenediamine removed from the filtrate by distillation in vacuo. The residue was distilled, boiling point 115°-117°/0.9 mm Hg to yield N-isobutyrylethylenediamine whose identity was confirmed by examination of the NMR and IR spectra. The latter, 15 g., was suspended in 200 ml. of dry THF and a solution of 20 g. (ca. 0.5 mole) of lithium aluminum hydride in 200 ml. of dry THF was added dropwise. The mixture was refluxed for 23 hrs., the excess lithium aluminum hydride destroyed by hydrolysis. The insoluble material was removed by filtration, and the filtrate concentrated in vacuo to yield N-(2-methylpropyl)ethylenediamine as an oil, yield 37 g. The identity of the product was confirmed by examination of the NMR spectrum, and 5.8 g. (0.05 mole) thereof was then dissolved in 20 ml. of MeOH and a solution of 5.8 g. (0.055 mole) of cyanogen bromide in MeOH was added in dropwise fashion with cooling. The mixture was stirred for 1/2 hr. and then concentrated in vacuo to an oil. The latter was dissolved in methylene chloride and again concentrated in vacuo to aid in removal of last traces of MeOH. The NMR spectrum of the residue, an oil, confirmed the structure 1-(2-methylpropyl)-1H-imidazo-2-amine hydrobromide. This material was then condensed with ethyl oximinocyanoacetate substantially according to the method described in Procedure 1. The product was recovered by distillation of the solvent from the reaction mixture in vacuo. The residue was dissolved in water and acidified with acetic acid. The precipitate that formed was collected and air dried. The damp solid was recrystallized from methanol/ethanol, m.p. 242.5°243.5°d.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+].Cl>O>[CH2:17]([O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCBr
Reactant: O=C(O)CCCCC(=O)c1ccccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCOc1ccccc1C(=O)CCCCC(=O)O
Yield: 0 %

Procedure:
A mixture of 5-(2-hydroxybenzoyl)pentanoic acid (1.5 g, 6.75 moles), hexyl bromide (1.28 g, 7.75 moles), potassium hydroxide (1.3 g) and water (7 ml) is heated under reflux (5 hours). The reaction mixture is neutralized with hydrochloride acid and extracted with ether (3×30 ml). The ether extract is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on a silica gel column (hexane:ether: acetic acid; 74:25:1) to provide a crude product which on recrystallization from heptane gives 5-(2-n-hexyloxybenzoyl) pentanoic acid (1.0 g) as a white crystalline solid, m.p. 64°-65° C.
Reaction SMILES: [Mg].II.[CH:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].Cl>O1CCCC1>[O:10]([C:11]1[CH:16]=[CH:15][C:14]([C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])=[CH:13][CH:12]=1)[C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask containing 33.6 g. of magnesium and a few crystals of iodine, is added 50 to 70 ml. of a solution of 300 g. of 4-bromodiphenyl ether in 500 ml. of absolute tetrahydrofuran. The remainder of the solution is added as needed to maintain a gentle reflux and the resulting mixture heated to reflux for 30 minutes. The resulting mixture is then added to a solution of trimethylacetyl chloride in 500 ml. of absolute tetrahydrofuran at a rate so as to maintain a temperature of from 40° to 50° C. The resulting mixture is then stirred at ambient temperature for 1 hour. 200 ml. of 2N. hydrochloric acid is then added. The organic layer is washed twice with 1 liter of 2N. sodium carbonate solution, dried and evaporated in vacuo to a liquid. The liquid thus obtained is distilled under reduced pressure to obtain p-phenoxypivalophenone, b.p. 136°-139° C. at 0.1 mm/Hg.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:9]=2[C:10]([CH3:12])=[N:11][C:6]=1[C:4]([NH:23][CH:24]([CH3:25])[C:26]([OH:28])=[O:27])=[O:5]
Reactant: C[C@H](N)C(=O)O
Reactant: CCOC(=O)c1nc(C)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NC(C)C(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 120 °C
Yield: 38.5 %

Procedure:
A mixture of 7-hydroxy-4-methyl-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (50 mg, 0.16 mmol) and L-alanine (146 mg, 1.63 mmol) in 0.5 M sodium methoxide/methanol (2.6 mL) was heated at 120° C. in a microwave vessel for 3 h before it was cooled to room temperature and concentrated in vacuo. Water was added to the residue and extracted four times with dichloromethane until no UV spot in the dichloromethane layer. The remaining aqueous layer was acidified to pH=3 with 1N HCl (2 mL). The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a white solid (22 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.98 (br s, 1H), 9.06 (d, J=7.4 Hz, 1H), 8.15 (m, 2H), 7.61 (m, 3H), 4.54 (m, 1H), 2.88 (s, 3H), 1.49 (d, J=7.4 Hz, 3H); MS: (+) m/z 358.04 (M+1).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43]([NH:45][C:46]3[C:47]([C:51](O)=O)=[N:48][NH:49][CH:50]=3)=[O:44])[C:37]=2[O:36][CH2:35][CH2:34]1.[NH2:54][C:55]1[CH:56]=[C:57]([C:62]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)=[O:63])[CH:58]=[CH:59][C:60]=1[NH2:61]>>[N:64]1([C:62]([C:57]2[CH:58]=[CH:59][C:60]3[NH:61][C:51]([C:47]4[C:46]([NH:45][C:43]([C:42]5[C:37]6[O:36][CH2:35][CH2:34][O:33][C:38]=6[CH:39]=[CH:40][CH:41]=5)=[O:44])=[CH:50][NH:49][N:48]=4)=[N:54][C:55]=3[CH:56]=2)=[O:63])[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1
Reactant: O=C(Nc1c[nH]nc1C(=O)O)c1cccc2c1OCCO2
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1N
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(C(=O)N3CCOCC3)ccc2[nH]1)c1cccc2c1OCCO2

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid (Example 97A) and (3,4-diamino-phenyl)-morpholin-4-yl-methanone (Example 94B) to give 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid {3-[5-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-amide (15 mg) as a beige solid. (LC/MS: Rt 2.89, [M+H]+ 475.20).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) in dry tetrahydrofuran (THF, 8 ml) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, N,N-dimethyl carbamoyl chloride (265 mg/ml, 3.14 mM) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 8k as solid. Yield: 0.796 g, 76.19%.
Reaction SMILES: [N:1]1([CH:10]([C:14]([OH:16])=[O:15])[C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([CH3:34])=[C:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[CH2:35](OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)[CH3:36]>C(Cl)(Cl)Cl>[C:14]([CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:11]([NH:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([CH3:34])=[C:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:13])([O:16][CH2:35][CH3:36])=[O:15]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: O=C(O)C(C(=O)O)n1ccc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(C)CSC12)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The monoethyl ester of 1H-indol-1-ylmalonic acid (3.96 mmole), (3.96 mmole) of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester and (3.96 mmole) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) are mixed in 50 ml of hydrocarbon stabilized chloroform. The mixture is stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with chloroform, washed with dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate and water. The chloroform solution is dried over magnesium sulfate, filtered and evaporated to dryness to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.Cl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=Cc1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(NN=Cc2ccccn2)cc1

Procedure:
2.2 g of 2-pyridinecarbaldehyde was added to a mixture of 3.6 g of p-chlorophenylhydrazine hydrochloride and 9.8 g of sodium acetate in 60 ml of 50% by volume aqueous ethyl alcohol. The mixture was refluxed for 10 minutes, cooled and the precipitate crystallized from ethyl alcohol to give 2, as yellow crystals, mp 184°-186° C.