Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.C(N(CC)[C:24]([C:26]1[C:27]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH3:45])=[CH:38][C:37]=2[O:46][CH3:47])=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[CH:29]=[CH:30][CH:31]=1)=[O:25])C>C1COCC1>[CH:33]([O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]2[C:27]=1[C:36]1[C:37]([O:46][CH3:47])=[CH:38][C:39]([O:42][CH2:43][CH2:44][CH3:45])=[CH:40][C:41]=1[C:24]2=[O:25])([CH3:35])[CH3:34]
Reactant: CCCOc1ccc(-c2c(OC(C)C)cccc2C(=O)N(CC)CC)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OC(C)C)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Prepare LDA reagent by reacting n-butyl lithium and diisopropylamine as in Example 7C to obtain 0.05 mole in THF (50 mL) at 0° C. At 0° C., dropwise add N,N-diethyl-6-isopropyloxy-2'-methoxy-4'-propyloxy-biphenyl-2-carboxamide (4.3 g, 0.011 mole) in THF (20 mL). Warm the mixture to ambient temperature, stir for 1 hour then heat to reflux for 1.5 hours. Workup the mixture as in Example 7C and chromatograph eluting with 50%/50% EtOAc/hexane to give the title compound as a red solid (2.6 g, 63%). m.p. 114°-116° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Br)ccc1CNCc1ccccc1
Reactant: O=C(Cl)Cc1cccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N(Cc1ccccc1)Cc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
580 mg of benzyl-(4-bromo-2-chlorobenzyl)amine are dissolved in 10 ml of CH2Cl2 (anhydrous) and treated first with 300 μl of pyridine, then with 330 mg of 2-thiophen-2-ylacetyl chloride. The mixture is stirred at RT for 4 h, then diluted with 100 ml of CH2Cl2 and washed with 50 ml of a saturated aqueous Na2CO3 solution. It is dried over MgSO4 and the solvent is removed in vacuo. It is chromatographed on silica gel using DIP and 490 mg of a colorless oil are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:25])[NH:23][CH2:22][CH2:21][NH:20][C:19]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:23]2[CH2:22][CH2:21][NH:20][C:19](=[O:24])[C:18]2([CH3:25])[CH3:17])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)NCCNC1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCNC(=O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
A mixture of intermediate 100.2 (Step 100.2) (18.4 g, 64 mmol), 3,3-dimethyl-piperazin-2-one (Step 108.4) (9 g, 70 mmol, 1.1 equiv) and Cs2CO3 (27.1 g, 83.2 mmol, 1.3 equiv) in DMF (75 ml) was stirred for 12 h at rt, quenched by addition of H2O (500 mL) and filtered to afford 14.5 g of the title compound as an off-white solid. Title compound: ESI-MS: 335.2 [M+H]+; tR=2.22 min (System 1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C=O)C.[CH3:10][C:11]1([CH3:23])[O:16][C:15](=[O:17])[CH:14]=[C:13]([CH2:18][C:19](=[O:22])[CH2:20]Cl)[O:12]1>C(OCC)(=O)C>[CH3:10][C:11]1([CH3:23])[O:16][C:15](=[O:17])[CH:14]=[C:13]([CH2:18][C:19](=[O:22])[CH2:20][N:1]=[N+:2]=[N-:3])[O:12]1
Reactant: CC1(C)OC(=O)C=C(CC(=O)CCl)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C=C(CC(=O)CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
195 mg (3.0 mmol) of sodium azide were added to 2 ml of a DMF solution containing 328 mg (1.5 mmol) of 2,2-dimethyl-6-(3-chloro-2-oxopropyl)-1,3-dioxin-4-one prepared in Example 1, followed by stirring at room temperature for 10 minutes. Afterward, the solution was poured into ice water, extracted with ether, and then dried with anhydrous magnesium sulfate. After ether was distilled off, the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=1:1), thereby obtaining 278 mg (yield 82%) of 2,2-dimethyl-6-(3-azido-2-oxopropyl)-1,3-dioxin-4-one.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=1.[NH4+].[OH-]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]2[N:17]=[C:1]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[NH:18][C:13]=2[CH:12]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc2nc(-c3ccncc3)[nH]c2c1
Yield: 49.1 %

Procedure:
To a mixture of isonicotinic acid (4.9 g., 0.04 mol) and 4-chloro-o-phenylenediamine (5.8 g., 0.041 mol) was added polyphosphoric acid (20 ml.). The mixture was heated to 200° and maintained at this temperature for 45 min. After cooling, the reaction mixture was poured onto ice and the solution made basic with conc. NH4OH. The resulting yellow solid was removed by filtration, dissolved in isopropanol, filtered and the filtrate concentrated to a solid. After recrystallization from EtOH-H2O, 4.5 g. of 5-chloro-2-(4-pyridyl)benzimidazole (49.1%) was obtained; m.p. 306-307.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: COCOC(C)Cc1ccc(Br)cc1
Reactant: BrCc1ccc(Br)cc1
Product: COCOC(C)Cc1ccc(Cc2ccc(Br)cc2)cc1

Procedure:
In accordance with Example 19-(2), but using 1-bromo-4-[2-(methoxymethoxy)propyl]benzene instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and 1-bromo-4-(bromomethyl)benzene instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, a crude product of 1-bromo-4-{4-[2-(methoxymethoxy)propyl]benzyl}benzene was afforded as a yellow oil.
Reaction SMILES: Cl.Cl.Cl.[OH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1[N:11]1[CH2:16][CH2:15][C:14]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>C(O)C>[I:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:8]2[CH2:9][CH2:10][CH:5]([OH:4])[CH:6]([N:11]3[CH2:16][CH2:15][C:14]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:19][CH2:18][CH2:17]4)[CH2:13][CH2:12]3)[CH2:7]2)=[CH:35][CH:34]=1
Reactant: ClCc1ccc(I)cc1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC1CCN(Cc2ccc(I)cc2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of the hydrochloride of 21c (250 mg, 0.67 mmol), potassium carbonate (463 mg, 3.35 mmol) and 4-iodobenzyl chloride (298 mg, 1.00 mmol) in absolute ethanol (25 mL) was refluxed for 16 h. When the mixture had cooled, salts were filtered off and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and the solution was successively washed with water (25 mL) and brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated. The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50) and (13e) was obtained as a colorless oil (226 mg, 52%). The hydrochloride was prepared in a satd HCl/ether soln and recrystallized twice from 50% isopropyl alcohol-hexanes to yield a yellow powder; mp 256.3° C.; 1H NMR (CDCl3) δ1.56-2.18 (2 m, 8, 2 N--C H2 --C H2), 2.40-2.45 (d, 2H, Ar--C H2 --CH2, J=10.1 Hz), 2.51-2.60 (m, 2, C H2 --CHOH), 2.72-2.78 (m, 4, Ar--CH2 -C H2 --C H2), 2.84-2.97 (t, 2, N--C H2 --CH2 --CHOH, J=11.9 Hz), 3.05-3.50 (d, 2, CHN--C H2 --N, J=10.4 Hz), 3.40-3.55 (m, 4, C H--OH+Ar--CH2 --N+CHN), 3.81 (s, 1, OH), 7.22-7.02 (m, 4, arom.), 7.42-7.46 (d, 2, arom., J=7.7 Hz), 7.63-7.67 (d, 2, arom., J=8.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CC([N:20]([C@@H:24]([C:27](NC1C=NC(OC2C=CC(C#N)=C(C(C)C)C=2)=CC=1)=[O:28])[CH2:25]C)[C:21](=O)[O-:22])(C)C.Cl>ClCCl>[CH3:25][C@H:24]1[NH:20][C:21](=[O:22])[N:13]([C:12]2[CH:14]=[CH:15][C:9]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:10][CH:11]=2)[C:27]1=[O:28]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1)N(C(=O)[O-])C(C)(C)C
Reactant: Cc1cccc(Oc2ccc(N)cc2)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 4-[(3-methylphenyl)oxy]aniline (90 mg, 0.45 mmol) in dichloromethane (1 mL) was added with shaking at 35° C. an aliquot of approximately 1/3 of solution 1 slowly via syringe (over ca. 1 min). After 30 min, HCl (ca. 0.8 mL) was added and the heterogeneous mixture was heated at 100° C. for 2 hours with shaking, allowing the dichloromethane to distill off through a glass capillary. After cooling to room temperature the aqueous HCl was pipetted off and the residue dried under vacuum. The residue was purified by silica gel chromatography (Biotage instrument, 10 g column) eluting with 0-100% EtOAc/cHex to give after drying the title compound as a solid (30 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[C:15]([NH:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:16]>>[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[C:15]([NH:17][C:18]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=1)=[O:19])=[O:16]
Reactant: O=C(NC(=O)c1c(F)cccc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(C(F)(F)F)cn1

Procedure:
A portion of 5-trifluoromethyl-2-aminopyridine is dissolved in an inert organic solvent, and to the solution is added a portion of 2,6-difluorobenzamidocarboxylic acid, 4-nitrophenyl ester. The reaction mixture is stirred at elevated temperature for a period of time, after which the reaction mixture is evaporated to dryness under vacuum, and the product named in the heading above, identical to the product of Example 1, is isolated by recrystallization.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:9][CH:8]=1.CN(C)[CH:34]=[O:35]>O1CCCC1>[CH:34]([C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:9][CH:8]=1)=[O:35]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)n1COCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C=O)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 33.1 %

Procedure:
n-Butyl lithium (2.5 M) in hexanes (1.6 mL, 4.00 mmol) was added dropwise to a stirring solution of (S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared by methods described in WO 2008/021928, WO 2008/021936 and WO 2008/021927)(1.70 g, 3.81 mmol) in tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 7 min, and then quenched with dimethylformamide (0.59 mL, 7.6 mmol) in one portion. The mixture was warmed to room temperature by removing the cooling bath, allowed to stir for 1 h, diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (0 to 100% ethyl acetate in hexanes) to afford (S)-tert-butyl 2-(5-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.26 mmol, 33% yield) as a yellow oil and a 2:3 mixture of regioisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:25]3[CH2:24][CH2:23][N:22]([CH2:26][C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])[CH2:21][CH2:20]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCOCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(4-morpholido)-2-piperazinoethanone to give 4-chloro-N-(4-{2-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide, using general procedure A. Amorphous off-white solid. MS 492.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC)c1nc(N)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CON=C(C(=O)O)c1nc(N)sc1C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.5 %

Procedure:
A mixture of ethyl 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 4.0 g.), 2N-aqueous sodium hydroxide (25 ml.), ethanol (30 ml.) and tetrahydrofuran (15 ml.) was stirred at room temperature for 75 minutes. The reaction mixture was adjusted to pH 6 with hydrochloric acid, and the organic solvent was distilled off in vacuo. The remaining aqueous solution was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried to give 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[N:7]([C:15]2([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[N:7]([C:15]2([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=3[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:16]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OC(C)=O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OC(C)=O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 69.1 %

Procedure:
With 500 mg of the compound obtained in Step 137-3 (Isomer B) and 329 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 526 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[CH:32]=[CH:31][CH:30]=1.[OH2:38]>CN(C)C=O>[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[CH:32]=[CH:31][CH:30]=1)([OH:38])=[O:22]
Reactant: O
Reactant: OCCCCCCc1cccc2cncn12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCc1cccc2cncn12
Reaction time: 6 h

Procedure:
Pyridinium dichromate (0.94 g) is added as a solid to a solution of 5-(6-hydroxyhexyl)-imidazo[1,5-a]pyridine (123 mg) in 10 ml of N,N-dimethylformamide at 25° under nitrogen. The solution is stirred for 6 hours, poured into 150 ml of water and extracted with methylene chloride (5×20 ml). The organic extracts are washed with 1 N sodium hydroxide. Acidification of the aqueous phase to pH=6, extraction with methylene chloride and drying over sodium sulfate/magnesium sulfate yields 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine of Example 2 melting at 145°-146°.
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:13][C:14](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([N:13]=[C:14]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCNC(=N)N
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 4.5 g. of sodium, 38.4 g. of n-hexylguanidine sulfate, and 25.4 g. of n-hexyl isocyanate, there was obtained 11.1 g. of 1-n-hexylamidino-3-n-hexylurea having the structural formula ##EQU62## as a white crystalline solid which melted at 75-78°C. The solubility of this base in water at 25°C. was less than 0.25 per cent. In 95 per cent ethyl alcohol at 25°C. it was soluble to the extent of 5 per cent (w/v); a precipitate formed when the 5 per cent alcoholic solution was diluted with four volumes of water.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:30]2[O:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OC(=O)C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][C:22]2[C:30]3[O:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:18]=1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)c1nc2cccc(CBr)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
1.8 g of 4-(2-quinolinylmethyloxy)phenol, 1.98 g of ethyl 7-bromomethylbenzoxazole-2-carboxylate and 1.0 g of potassium carbonate are combined in 100 ml of acetone and refluxed for 18 hours. The mixture is cooled, diluted with ethylacetate and filtered. The filtrate is concentrated and the crude product purified by flash chromatography on silica gel in 5% ethanol in chloroform/hexane (1:1) to give ethyl 7-(4-(quinolin-2-ylmethoxy)phenoxymethyl)benzoxazole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: Cc1cccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[S:6][C:7]=1[C:8](=[O:10])[CH3:9].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:8]([C:7]1[S:6][C:5]([N:11]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:18](=[O:20])[CH3:19])=[N:4][C:3]=1[CH3:2])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1sc(Nc2cnccn2)nc1C
Agent: Cl
Product: CC(=O)c1sc(N(C(C)=O)c2cnccn2)nc1C
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
In a tube, 1-[4-Methyl-2-(pyrazin-2-ylamino)-1,3-thiazol-5-yl]ethanone, hydrochloride salt (500 mg; 1.85 mmol; 1 eq.) is mixed with acetic anhydride (2.16 ml; 22.90 mmol; 12.40 eq.). The tube is sealed and is heated at 150° C. with an oil bath. After 15 min, the mixture becomes yellow. The reaction is complete. The solvents are removed and N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N-pyrazin-2-ylacetamide is used as such without further purification (510.3 mg; quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32]([CH:37]=O)=[CH:31]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:37][C:32]4[NH:33][C:34]5[C:30]([CH:31]=4)=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:36][CH:35]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCOCC4)ccc3[nH]2)cc1

Procedure:
6-(4-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([OH:30])[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]OC)=[CH:36][CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: COCc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.55 mmol), 1-fluoro-4-methoxymethyl-benzene (103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.414 g; 1.65 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h and purified by prep. HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17]>>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9](=[O:18])[CH2:6][C:2]#[N:1]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: Nc1cc[nH]n1
Product: N#CCC(=O)c1ccc(F)cc1Cl
Yield: 60 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 2-chloro-4-fluoro-benzoic acid methyl ester (0.7 g, 3.7 mmol, 1.0 eq). The crude product was extracted with DCM and used in the following step without further purification (0.4 g, yield: 60%).