Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]1[C:7]2[CH2:14][C:10]3[S:11][CH:12]=[CH:13][C:9]=3[C:8]=2[NH:22][N:21]=1
Reactant: COc1ccccc1C(=O)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1n[nH]c2c1Cc1sccc1-2
Temperature: 25 °C
Yield: 89.2 %

Procedure:
5-(2-Methoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.53 g, 8.3 mmol), hydrazine monohydrate (0.65 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (20 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(2-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (2 g, 7.4 mmol) as white solid in 89% yield.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Cl-].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][Zn+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:6]1[C:2]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:4][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1ccc(C[Zn+])cc1Cl
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A sealable reaction vessel containing a suspension of ethyl 3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate (0.560 g, 1.40 mmol), 0.500 M 3,4-dichlorobenzylzinc chloride in THF (3.368 mL, 1.684 mmol) and THF (2.06 mL, 25.4 mmol) was purged via vacuum/backfilling with argon. To this suspension was added tetrakis(triphenylphosphine)palladium(0) (81.07 mg, 0.07016 mmol), the vial was capped, and the resulting black suspension was stirred at 95° C. overnight. The reaction mixture was adsorbed to celite in vacuo, and the solid thus obtained was purified via column chromatography (eluent: 0-15% EtOAc:hexane) to afford ethyl 4-bromo-3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)thiophene-2-carboxylate (323 mg, 50%). LCMS: (FA) ES+ 478, 480, 482; 1H NMR (400 MHz, DMSO) δ 7.53 (d, J=8.3 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.3, 2.1 Hz, 1H), 4.36 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 3.75-3.70 (m, 4H), 3.17-3.12 (m, 4H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[N:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[CH:19]=[CH:18][C:17]([S:20][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:16][CH:15]=1
Reactant: Sc1ccncc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2ccncc2)cc1C#N
Reaction time: 3 h
Yield: 58.3 %

Procedure:
A mixture of 4-nitro-phthalonitrile (17.28 g), pyridine-4-thiol (10.68 g) and potassium carbonate (25.17 g) in N,N-dimethyl-formamide (160 ml) was heated to 85 C and stirred for 3 h. After cooling, the reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. Filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 15-30% of ethyl acetate in methylene chloride) to give the title compound 13.29 g. 1H NMR (200 MHz, CDCl3) δ 8.59 (d, J=6.2 Hz, 2H), 7.68 (m, 3H), 7.24 (d, J=6.3 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 72.2 %

Procedure:
A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,4-diamine (Intermediate 126, 3.7 g, 7.93 mmol), iron (2.66 g, 47.58 mmol) and NH4Cl (0.318 g, 5.95 mmol) was heated in ethanol (120 mL) and water (40 mL) at reflux for 2.5 h. The mixture was then cooled, filtered and concentrated. The solids were triturated in 5% CH3OH/CH2Cl2 (100 mL) for 15 minutes and then filtered. The filtrate was combined with the concentrated, filtered reaction mixture, washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (2.50 g, 72%) as a brown gum; 1H NMR (CDCl3): 1.90-1.99 (2H, m), 2.04-2.13 (2H, m), 2.25 (6H, s), 2.37-2.42 (2H, m), 2.67 (3H, s), 2.92-2.98 (2H, m), 3.25 (2H, t), 3.83 (3H, s), 4.00 (2H, s), 4.21 (2H, t), 6.70 (1H, s), 6.79 (1H, d), 7.48 (1H, s), 7.97 (2H, d), 8.30 (1H, d); m/z: ES+ MH+ 437.39.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21]([S:24]C(C)C)([CH3:23])[CH3:22].O>O1CCCC1>[CH:21]([S:24][C:5]1[CH:4]=[C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])[O:7][C:6]=1[C:8]([OH:10])=[O:9])([CH3:23])[CH3:22]
Reactant: C[Si](C)(C)c1ccc(C(=O)O)o1
Reactant: CC(C)SC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Sc1cc([Si](C)(C)C)oc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 25.01 g (136.0 mmol) of 5-trimethylsilyl-2-furancarboxylic acid (Carpenter, A. J. and Chadwick, D. J., Tetrahedron Lett., 26, 1777 (1985)) in 50 mL of dry tetrahydrofuran is added over 10 minutes to a -76° C. solution of freshly generated lithium diisopropylamide (328.0 mmol, 2.41 equiv) in dry tetrahydrofuran (175 mL) under nitrogen atmosphere and the resulting mixture is stirred at -76° to 65° C. for 1.5 hours. The reaction is recooled to -76° C. and treated with 23.58 g (151.0 mmol, 1.11 equiv) of diisopropyl sulfide in 25 mL of tetrahydrofuran and the resulting mixture is stirred for 4 hours while slowly warming to room temperature. The reaction is poured onto 1.5 L of water and the aqueous mixture is extracted with diethyl ether (200 mL, 3x), treated with 400 g of ice, and acidified with concentrated hydrochloric acid. The resulting precipitate is collected by vacuum filtration and recrystallized from diethyl ether/cyclohexane to give 18.22 g (35.14 g theo., 52%) of analytically pure 3-isopropylthio-5-trimethylsilyl-2-furancarboxylic acid as a tan solid; mp 181°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[O:4][N:3]=1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:6]=[C:5](/[CH:7]=[N:15]/[S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[O:4][N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(Br)no1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1cc(Br)no1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 3-bromo-isoxazole-5-carbaldehyde (182 mg, 1.03 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (150 mg, 121 mmol) in CH2Cl2 (2 mL) was added titanium (IV) isopropoxide (0.667 mL, 2.28 mmol) and the mixture was warmed at reflux. After 22 hours, the solvent was concentrated in vacuo and the remaining solution was diluted with EtOAc (33 mL) and saturated aqueous NaCl (6 mL) was added. The resultant heterogeneous mixture was stir at room temperature. After 30 minutes, the mixture was filtered through a pad of diatomaceous earth. The EtOAc layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to afford 2-methyl-propane-2-sulfinic acid 1-(3-bromo-isoxazol-5-yl)-meth-(E)-ylideneamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 5 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 4 (5% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.71 and 3.17 (2d, 6H), 2.85 and 3.09 (2t, 2H), 3.58 and 4.21 (2t, 2H), 4.48 and 5.09 (2s, 2H), 6.36 and 6.84 (2d, 1H), 6.96-7.25 (m, 3H), 7.57-8.15 (m, 5H), 8.62-8.69 (m, 2H); MS (ESI) m/z 443 ([M+H]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OC)=[O:11]>[O-2].[Mn+2]>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11]
Reactant: COC(=O)c1cc2ncccc2[nH]1
Agent: [Mn+2]
Agent: [O-2]
Product: O=Cc1cc2ncccc2[nH]1

Procedure:
This was prepared from methyl 1H-pyrrolo[3,2-b]pyridin-2-carboxylate (0.1 g) and amine (1d) by the method of Example 16c, (except that the alcohol was stirred with manganese (II) oxide overnight) and used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C@H:16]([O:26][CH2:27][CH2:28][CH3:29])[C@H:17]([C@@H:23]([OH:25])[CH3:24])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:18]([C@H:17]1[C@H:23]([CH3:24])[O:25][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:14][CH2:15][C@@H:16]1[O:26][CH2:27][CH2:28][CH3:29])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](CCC(C)C)[C@H](C)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCCO[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Reaction time: 7 h
Yield: 59.2 %

Procedure:
A solution of (2S,6S,7S)-2-((tert-butoxycarbonyl)amino)-7-((S)-1-hydroxyethyl)-10-methyl-6-propoxyundecanoic acid (627 mg, 1.50 mmol) in anhydrous DCM (80 mL) was added over 12 h using a syringe pump to a stirred solution of MNBA (1.03 g, 3.00 mmol) and DMAP (1.10 g, 9.01 mmol) in DCM (150 mL) at room temperature. Stirring was continued for an additional 7 h then the reaction mixture was treated with Celite® (5 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (80 g SiO2, 0→30% EtOAc/hexanes) to afford the title compound (355 mg, 0.888 mmol, 59%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.06 (d, J=8.2 Hz, 1H), 4.70 (dq, J=10.1, 6.4 Hz, 1H), 4.24-4.14 (m, 1H), 3.50 (app dt, J=9.0, 6.4 Hz, 1H), 3.28-3.19 (m, 1H), 3.13 (app dt, J=8.8, 6.6 Hz, 1H), 2.30-2.18 (m, 1H), 2.11 (dddd, J=15.6, 10.1, 7.9, 5.2 Hz, 1H), 1.87 (app dq, J=13.1, 4.6 Hz, 1H), 1.78-1.35 (m, 16H), 1.31 (d, J=6.3 Hz, 3H), 1.24-1.03 (m, 3H), 0.96-0.75 (m, 10H); 13C NMR (101 MHz, CDCl3) δ 173.11, 154.94, 79.93, 79.70, 73.53, 70.41, 52.46, 46.66, 34.41, 33.63, 29.03, 28.75, 28.33, 26.26, 23.30, 22.61, 22.44, 19.26, 17.80, 10.88; ESIMS m/z 422 ([M+Na]+).
Reaction SMILES: [NH2:1][C:2]1([CH2:8][O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1>>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][C:2]2([NH:1][CH2:30][CH2:29][C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC1(COC(c2ccccc2)c2ccccc2)CCCCC1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCNC2(COC(c3ccccc3)c3ccccc3)CCCCC2)cc1

Procedure:
The title compound was prepared as described in Example 1 using 1-amino-1-diphenylmethoxymethylcyclohexane (see Preparation 3) and 4-methoxyphenethyl bromide. The title compound was obtained as a colourless oil (0.88 g, 68%) which was characterised from its 1H-n.m.r. spectrum.
Reaction SMILES: C[Mg]I.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2(C#N)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].CC[O:21][CH2:22][CH3:23]>>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:22](=[O:21])[CH3:23])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: CCOCC
Agent: C[Mg]I
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methylmagnesium iodide (3M solution in ether; 100 ml) was added dropwise at 0° C. under nitrogen to a stirred solution of 1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (48 g) in ether (100 ml), then the mixture was stirred at ambient temperature for 24 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions to an ice-cold mixture of water (200 ml) and concentrated hydrochloric acid (125 ml). The mixture was heated at 95° C. with occasional stirring for 1 hour, then it was allowed to cool to ambient temperature. The product was extracted into ether (5×100 ml), then the combined extracts were washed with water (2×100 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was distilled to give 1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellow oil (31.9 g), b.p. 124-128° C/0.5 mbar.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C.Cl.[NH2:35][C@H:36]([C@H:44]1[O:48][C:47](=[O:49])[C@H:46]([CH2:50][CH2:51][C:52]([F:55])([CH3:54])[CH3:53])[CH2:45]1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.C(OCC)C>[F:55][C:52]([CH3:54])([CH3:53])[CH2:51][CH2:50][C@H:46]1[C:47](=[O:49])[O:48][C@H:44]([C@@H:36]([NH:35][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:13])[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:45]1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CC(C)(F)CC[C@@H]1C[C@@H]([C@@H](N)Cc2ccccc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(F)CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of quinoxaline carboxylic acid (5.05 g, 29.0 mmol) in methylene chloride (100 mL) was added dimethylaminopyridine (DMAP) (3.55 g, 29.0 mmol) and EDCl (5.55 g, 29.0 mmol). The solution was stirred 10 minutes, then the product from Method D, above, (5.68 g, 19.4 mmol) was added in one portion. The solution was stirred for 12 hours, then diluted with diethyl ether and washed with saturated aqueous brine. The organics were dried over magnesium sulfate, and then filtered and concentrated. The crude product was purified by silica gel chromatography to yield the title compound (5.62 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[CH2:18]([CH2:22][C:23](=O)[CH3:24])[C:19]([CH3:21])=O>C(O)C>[CH:11]1([C:4]2[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]3[C:23]([CH3:24])=[CH:22][CH:18]=[C:19]3[CH3:21])[N:3]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)c1[nH]c(C2CC2)nc1N
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c(C2CC2)nc1-n1c(C)ccc1C
Yield: 95.6 %

Procedure:
A suspension of methyl 4-amino-2-cyclopropylimidazole-5-carboxylate (Example 40, 5.72 g, 0.032 mol) in ethanol (40 mL) was treated with acetic acid (25 mL) and the mixture refluxed to effect solution. To the hot solution was added acetonylacetone (5.41 g, 0.047 mol) and the whole stirred and refluxed for 18 hours. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2 to afford 7.93 g of the title compound methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole-5-carboxylate. 1H-NMR (CDCl3) 5.85 (s, 2H), 3.68 (s, 3H), 2.0 (s, 6H), 1.80-2.0 (m, 1H), 1.0-1.18 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5](I)=[C:6]([O:8][CH3:9])[CH:7]=1.C([Mg]Cl)(C)C.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:5]2[CH:4]=[C:3]([F:11])[C:2]([Cl:1])=[CH:7][C:6]=2[O:8][CH3:9])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(Cl)c(F)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)c(Cl)cc2OC)c(N)n1

Procedure:
To a solution of 5-chloro-4-fluoro-2-iodoanisole (1.0 g, Example 375) was added isopropylmagnesium chloride (1.92 mL, 2M in tetrahydrofuran, Aldrich) and the reaction was stirred at −40 to −35° C. for 40 minutes before 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (170 mg, Example 1) in tetrahydrofuran (4 mL) was added. The resulting reaction was quenched with aqueous ammonium chloride. Work-up and purification as in Example 47 gave (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 342.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[OH:43].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:51][CH2:52][CH2:53][O:54][CH3:55].[I-].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:51][CH2:52][CH2:53][O:54][CH3:55]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Cl)c(O)c2)cc1
Reactant: COCCCCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Temperature: 80 °C
Reaction time: 20 h

Procedure:
The solution of 0.150 g of tert-butyl 3-(4-chloro-3-hydroxybenzyloxy)-4-{4-[3-(2-methoxy-benzyloxy)propoxy]phenyl}piperidin-1-carboxylate in 1.5 ml of N,N-dimethylformamide is admixed successively with 0.104 g of potassium carbonate, 0.082 ml of 1-chloro-3-methoxypropane and 0.004 mg of potassium iodide, and stirred at 80° C. over 20 hours. The reaction mixture is admixed with 1M aqueous sodium hydrogencarbonate solution (25 ml) and extracted with ethyl acetate (2×25 ml). The organic phases are washed with water (2×25 ml) and brine (1×25 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.44.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:10])=[N:3]1.[Na].O>C(O)C>[CH3:1][C:2]1([CH3:11])[NH:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([CH3:10])[NH:3]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1CC(C)(C)NC(C)(C)N1
Temperature: 25 °C

Procedure:
A sample of 27.4 grams 2,2,4,4,6-pentamethyl-2,3,4,5-tetrahydropyrimidine was dissolved in 50 grams of ethanol. To the ethanolic solution was added 6.9 grams of sodium metal at such a rate that a temperature of 70°-80° C. was maintained. After the addition was completed, the mixture was heated for one hour at 85°-95° C. The mixture was allowed to cool to room temperature and water added to the mixture. The organic layer was extracted with toluene, the toluene extract washed with water, dried, and the toluene removed, yielding 2,2,4,4,6-pentamethyl-hexahydroprimidine.
Reaction SMILES: [N+](C1C=CC(C[C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:34])[C:13]3(C(OC(=O)C)C3C=CC4N5C=CN=C5SC=4C=3)Br)[C:10]=2[C:35]([O-:37])=[O:36])=CC=1)([O-])=O.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[O:34]=[C:12]1[N:11]2[CH:14]([S:15][CH:9]=[C:10]2[C:35]([OH:37])=[O:36])[CH2:13]1
Reactant: CC(=O)OC(c1ccc2c(c1)sc1nccn12)C1(Br)C(=O)N2C(C(=O)[O-])=C(Cc3ccc([N+](=O)[O-])cc3)SC21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C1=CSC2CC(=O)N12
Temperature: 3 °C

Procedure:
4-Nitrobenzyl-6-[(acetyloxy) (imidazo[2,1-b][1,3]benzothiazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg, 1.4 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and 0.5 M phosphate buffer (pH 6.5, 20 mL) and hydrogenated over Pd/C (10%) at 40 psi pressure for 6 hrs. The reaction vessel was covered with foil to exclude light. The reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was concentrated and the aqueous layer was washed with ethyl acetate. The aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 180 mg, 36%; as yellow crystals; mp 235° C.; (M+H+Na) 378.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].O>ClCCl>[CH2:27]([O:26][C:25]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1)=[O:29])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (500 mg) and triethylamine (0.6 ml) are dissolved in dichloromethane (10 ml) and thereto is added dropwise ethyl chlorocarbonate (0.31 ml) gradually. The mixture is stirred at room temperature for 2 hours and poured into water. The mixture is extracted with chloroform, dried with sodium carbonate and purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1). The resultant is re-crystallized from ethanol/n-hexane to give 1-(1-ethoxycarbonyl-4-piperidinyl)-3,4-dihydrocarbostyril (0.1 g) as white powder, m.p. 82°-83° C.