Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.C([O-])=O.[Na+].C1OCCOCCOCCOCCOC1.I[C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:38]=1[O:47][CH:48]=[C:49]([C:51]1[C:60]([CH3:61])=[CH:59][C:58]2[C:57]([CH3:63])([CH3:62])[CH2:56][CH2:55][C:54]([CH3:65])([CH3:64])[C:53]=2[CH:52]=1)[CH3:50]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:61][C:60]1[C:51]([C:49]2([CH3:50])[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:38]=3[O:47][CH2:48]2)=[CH:52][C:53]2[C:54]([CH3:65])([CH3:64])[CH2:55][CH2:56][C:57]([CH3:63])([CH3:62])[C:58]=2[CH:59]=1
Reactant: COC(=O)c1ccc(I)c(OC=C(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Agent: [Pd+2]
Agent: C1COCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc2c(c1)OCC2(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 45 °C

Procedure:
A mixture of tributylamine (0.4 ml, 0.88 mmol), palladium diacetate (0.017 g, 0.083 mmol), formic acid (0.034 ml, 0.91 mmol), sodium formate (60 mg, 0.88 mmol), 15-crown-5 and methyl 4-iodo-3-[2-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyloxy]benzoate (429 mg, 0.83 mmol) in acetonitrile (10 ml) is heated at 45° C. for 8 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. 20 ml of water and 20 ml of ethyl ether are added. After separation of the phases by settling, the organic phase is washed twice with 20 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:8]=1[C:9]#[N:10].[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O>[NH2:15][C:12]1[CH:13]=[CH:14][C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ccc1OCc1cccc(F)c1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A mixture of 20A (108 mg, 0.4 mmol) and tin chloride (268 mg ,1.2 mmol) in EtOAc (4 ml) was heated to reflux for 15 h. The mixture was cooled to rt and triturated with EtOAc (2×60 ml). The filtrate was concentrated in vacuo. The combined EtOAc extracts were washed with NaHCO3 (1×30 ml), brine (1×30 ml), dried (MgSO4), filtered and concentrated in vacuo to give 20B (43 mg, 45% pure) which was used in next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([CH:35]=[N:36][OH:37])=[CH:33][CH:32]=1>>[F:26][C:23]([F:24])([F:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:37]/[N:36]=[CH:35]/[C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:41])[F:40])=[CH:39][CH:38]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccccc1C(F)(F)F
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Product: O=C(O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccccc1C(F)(F)F
Yield: 70 %

Procedure:
The title compound (0.404 g, 70%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and 4-trifluoromethyl-benzaldehyde oxime using a procedure similar to step 1 of example 6. mp=147.2-147.9° C.; mass spectrum −ES, (M−H) m/z 553. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 11.90 (bs, 1H), 8.38 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.86 (d, 1H), 7.77 (m, 7H), 6.81 (dd, 1H), 4.33 (t, 2H), 4.18 (t, 2H), 2.18 (m, 2H). Elemental analysis: Calcd. for C26H20F6N2O5: C, 56.32; H, 3.64; N, 5.05, Found: C, 55.83; H, 3.27; N, 4.88.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([NH:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Yield: 78 %

Procedure:
A suspension of 2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (2.0 g) in acetic anhydride (180 ml) and acetic acid (20 ml) was refluxed for 16 hours. The hot suspension was filtered and the filtrate was concentrated under reduced pressure until crystallization started. The precipitate was filtered off to give the pure title compound in 78% yield. The compound was characterized by its mass spectrum as follows: MS (m/z): 299 ([M+H]+, 100).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH2:7]([C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Reactant: CC(C)Cc1ncc(Br)s1
Product: Cc1ccccc1-c1cc(-c2cnc(CC(C)C)s2)cn2ccnc12

Procedure:
Example 189 was prepared using the procedure describe for Example 34, step 4, from 5-bromo-2-isobutylthiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.86 min.; (M+H)+: 348.0
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)C=C.Cl.CCOCC.C(N(CC)[C:25]1[CH:30]=CC=C[CH:26]=1)C>>[OH:4][C:5]1[C:6]([CH2:30][CH:25]=[CH2:26])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc2c(c1)CCCC2=O
Agent: Cl
Solvent: CCOCC
Product: C=CCc1c(O)ccc2c1CCCC2=O
Reaction time: 20.5 h
Yield: 60 %

Procedure:
A solution of 12.51 g (61.93 mmol) of 3,4-dihydro-6-(2-propenyloxy)-1(2H)-naphthalenone in 125 mL of N,N-diethylaniline was stirred and heated in a 225°-230° C. oil bath, for 20.5 hr. The resulting dark-amber solution was cooled and poured into 300 mL of cold 3N HCl. The mixture was worked-up with ether in the usual manner giving 12.29 g of a yellow solid which was a mixture of the 5- and 7-allyl isomeric hydroxy naphthalenones. This material was recrystallized from ethyl acetate giving the pure 5-allyl isomer in 60% yield, in several crops. The analytical specimen was a yellow solid, mp 145°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.[OH-].[Na+]>ClCCl.O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])=[CH:7][N:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CC2)cn1
Reaction time: 1 h

Procedure:
5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole) and 10 milliliters (ml) of pyridine were mixed together in 200 ml dichloromethane in a reaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acid chloride was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was added with 200 ml of 5% sodium hydroxide and 100 ml of water. The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 grams, after drying. The product was identified by IR and NMR as the title compound, having a melting point of 130°-131° C. This compound will be referred to as Compound 1.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH:4]([CH3:25])[CH:5]([C:8]1[CH:9]=[C:10]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7].CO.[OH-].[Na+].[Cl-].[Na+]>O>[CH3:26][N:2]([CH3:1])[CH2:3][CH:4]([CH3:25])[CH:5]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: CCC(c1cccc(OS(=O)(=O)c2ccc(C)cc2)c1)C(C)CN(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(c1cccc(O)c1)C(C)CN(C)C
Temperature: 31.5 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
To a stirred solution of [1RS,2RS]-toluene-4-sulfonic acid 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenyl ester (9 g, 0.02 mol) and methanol (27 ml), a solution of sodium hydroxide (4 g, 0.10 mol) and water (18 ml) was added at 20-25° C. and mixture was stirred at 28-35° C. for 20 hours. Reaction mixture was further stirred at 45-50° C. for 6 hours and solvent was distilled off. Resulting residue was dissolved in demineralised water (30 ml) at ambient temperature and washed with isopropyl ether (2×10 ml). Aqueous layer was separated and aqueous hydrochloric acid (7.3 ml, 30%) was added at 20-25° C. reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (2×50 ml). All ethyl acetate extracts were combined, washed with water, dried and solvent was distilled off to give 4.24 g of title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.[C:27](Cl)(=[O:30])[O:28][CH3:29].O>ClCCl>[CH3:29][O:28][C:27](=[O:30])[NH:19][CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([Br:1])[N:3]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)Cl
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1

Procedure:
To ((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methanamine (0.464 mmol, 150 mg) in dichloromethane (5 ml) at 0° C. were added triethylamine (0.464 mmol, 64.7 μl) and methyl carbonochloridate (0.505 mmol, 39 μl). After stirring at room temperature for one hour water was added. The organic layer separated, dried (Na2SO4) and concentrated in vacuo to give methyl((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (97 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH2:17][CH2:16]1)(C)(C)C.C(O)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[N:18]1[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccs2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: NC1CCN(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of 1.14 g (4.00 mmol) (1-thiazol-2-yl-piperidin-4-yl)-carbamic acid-tert-butyl ester in DCM (10 ml). The reaction solution was stirred for 1 h at RT and subsequently concentrated in vacuo. 1.02 g (0.34 mmol, 86%) 1-(thiazol-2-yl)piperidin-4-amine trifluoroacetate were obtained by crystallisation of the residue from an ethanol/EE-mixture.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28])=[C:18]([CH:26]=2)[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:39][OH:40].[O-]CC.[Na+]>C(O)C>[NH2:2][C:1](=[N:39][OH:40])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27](=[O:28])[N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])=[C:18]([CH:26]=2)[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:36][CH:37]=1
Reactant: NO
Reactant: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C(N)=NO)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
A stirred solution of ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate (970 mg, 1.9 mmol) in 20 mL of anhydrous ethanol is treated with hydroxylamine hydrochloride (400 mg, 5.7 mmol) and 21% sodium ethoxide solution in ethanol (2.1 mL, 5.7 mmol) and stiffed at 50° C. overnight. The reaction is concentrated in vacuo and purified by chromatography on silica gel (20 g) with 80-100% ethyl acetate/hexane followed by 0-10% methanol/ethyl acetate as the eluent to afford (a) ethyl 2-[5-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxy]acetate as a colorless foam;
Reaction SMILES: CN(C=O)C.[C:6]1([N:12]=[C:13]([O:23][C:24]2[CH:29]=CC=CC=2)[CH:14]=[CH:15]OC2C=CC=CC=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Na].[CH2:31]([SH:33])[CH3:32]>C(OCC)(=O)C>[C:6]1([N:12]=[C:13]([O:23][CH2:24][CH3:29])[CH:14]=[CH:15][S:33][CH2:31][CH3:32])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CCS
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(C=CSCC)=Nc1ccccc1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To DMF (5 ml) solution of phenyl N-phenyl-3-phenoxyacrylimidate (0.30 g) was added sodium salt of ethyl mercaptan (0.10 g) under ice-cooling, and stirred for three hours at the same temperature. Ethyl acetate (80 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. DMF (5 ml) and sodium salt of ethyl mercaptan (0.1 g) were added to the residue, and stirred for three hours at room temperature. Ethyl acetate (80 ml) was added to the reaction solution and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain ethyl N-phenyl-3-(ethylthio)acrylimidate (0.14 g) as yellow oil.
Reaction SMILES: C(N1CCC(CN2C3C4C=CC=CC=4N=CC=3N=[C:13]2[CH2:25][O:26][CH2:27]C)(O)CC1)(=O)C.[C:29]([N:32]1[CH2:37][CH2:36][C:35]([CH2:45][N:46]2[C:58]3[C:57]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[N:51]=[CH:50][C:49]=3[N:48]=[C:47]2[CH2:59]OCC)([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:33][CH2:34][C:35]([CH2:45][N:46]2[C:58]3[C:57]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[N:51]=[CH:50][C:49]=3[N:48]=[C:47]2[CH2:59][CH2:27][O:26][CH2:25][CH3:13])([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH2:36][CH2:37]1)(=[O:31])[CH3:30]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(C)=O)CC1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(C)=O)CC1
Product: CCOCCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(C)=O)CC1
Yield: 13 %

Procedure:
1-Acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (1.80 g, 4.68 mmol) was converted into 1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline according to the method described in Part A of Example 13. Purification by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) yielded 1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxyethyl)-1H-imidazo[4,5-c]quinoline (0.30 g, 13%) and recovered starting material, 1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (1.20 g).
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)CCN(C)C.C([Li])CCC.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.[C:30](=[O:32])=[O:31]>CCCCCC.O>[CH:28]1([C:30]([OH:32])=[O:31])[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: c1ccc2c(c1)CCCC2
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: O=C(O)C1CCCc2ccccc21
Reaction time: 0.25 h

Procedure:
A mixture of potassium tert-butoxide (74.13 g, 661 mmol) and N,N,N',N'-tetramethylethylenediamine (6.63M, 78.92 mL, 523 mmol) in 1.7 L of hexane was cooled to below -30° C. under a nitrogen atmosphere and then n-butyl lithium (1.6M, 327 mL, 523 mmol) was added over 15 minutes. The mixture was stirred for 15 minutes and 1,2,3,4-tetrahydronapthalene (7.36M, 85.27 mL, 623 mmol) was added. The mixture was stirred for 6 hours at 0° C. and then for 18 hours at between 0° and 20° C. The mixture was aerated with carbon dioxide for approximately 30 minutes and then approximately 1.2 L of water was added. The aqueous layer was separated, cooled in an ice-water bath and acidified with approximately 185 mL of 12N hydrochloric acid. The mixture was then extracted with ethyl acetate (2×1 L) and the combined ethyl acetate layers were dried (NaSO4). The mixture was filtered and concentrated. The residue was dissolved in 170 mL of formic acid and then the solution was diluted with 340 mL of water to give a crystalline product. The product was isolated by filtration, washed with 40 mL of water and dried. The dry material was dissolved in 0.74 L of ethyl acetate and the solution was washed with 0.5 L of water, dried (Na2SO4) and concentrated to give 1,2,3,4-tetrahydro-1-naphthoic acid (38.68 g, 219.6 mol), m.p. 74.4°-79.2° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr.CC(O)=O>CC(O)=O.C(OC(=O)C)C>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1ccccc1
Agent: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of acetophenone (500 mg, 4.16 mmol) in AcOH (20 mL) and catalytic amount of aq. HBr, 10% Br2/AcOH (2.12 mL) was added at 0° C. The reaction mixture was stirred for 2 h at r.t. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:9 EtOAc:hexane) to afford the title compound (825 mg, 4.1 mmol, 100%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](OC)=[O:16])=[O:12])[CH2:10][CH:5]2[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:3]1.[BH4-].[Li+].O>O1CCCC1>[OH:16][CH2:15][CH:14]([NH:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3][C:4]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:5]2[CH2:10]1)=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(NC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(CO)c1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Methyl α-[[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]benzeneacetate (0.15 g, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL). Lithium borohydride (14 mg, 0.64 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate) and powder was formed from hexane to obtain the title compound (0.13 g, yield 90%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[N:13][C:12]=2[CH3:24])=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[N:13][C:12]=2[CH3:24])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Liquid bromine (0.30 g, 0.097 ml, 1.89 mmol) was added drop wise to a stirred solution (5-(4-methoxyphenyl)-4-methylthiazol-2-yl)(piperidin-1-yl)methanone (5a, 0.5 g, 1.58 mmol) in acetic acid (6 ml) at 25° C. The resulting mixture was stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained after concentration was dissolved in ethyl acetate (50 ml). The mixture was then washed with saturated sodium bicarbonate solution (20 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound 5b (0.54 g, 86.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][CH:3]=1.CO.[C:14](O)(=O)[CH:15]=[O:16]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[N:8]=[C:15]([OH:16])[CH:14]=[N:9]2
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: Oc1cnc2cccc(Cl)c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
100 ml of triethylamine were added to the reduction product of 6-chloro-2-nitroaniline in methanol (assumed to be 8 mol), obtained as described under (a). The mixture was then heated to 50° C. 1,168 g (8 mol) of glyoxylic acid semiacetal ester were then added dropwise, over the course of 2 hours, to the mixture, thereby causing a slight exothermic reaction. The mixture was boiled for 2 hours under reflux, whereupon a solid product separated out. After 2 hours, the mixture was cooled to 0° C. and the precipitate was filtered off. 110 g (7.6% of theory) of 8-chloro-2-hydroxy-quinoxaline were obtained in the form of a light gray powder of melting point above 250° C. The mother liquor was concentrated, ether was added and the residue was filtered off. A further 583 g (40.6% of theory) were thus obtained. Accordingly, the total yield was 693 g (48% of theory). ##STR30##
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[N:12]3[CH:13]=[C:14]([C:17]4[C:18]([C:41]5[CH:50]=[CH:49][C:44]([C:45](OC)=[O:46])=[CH:43][CH:42]=5)=[N:19][N:20]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)=[CH:5][CH:4]=1.CSC1SC(C2N3C=C(C4C(C5C=CC(C(OCC)=O)=CC=5)=NN(C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)C=4)C=CC3=NC=2)=CC=1>>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[N:12]3[CH:13]=[C:14]([C:17]4[C:18]([C:41]5[CH:42]=[CH:43][C:44]([CH2:45][OH:46])=[CH:49][CH:50]=5)=[N:19][N:20]([C:22]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:21]=4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(SC)s4)n3c2)cc1
Agent: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(SC)s4)n3c2)cc1
Product: CSc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(CO)cc4)cn23)s1

Procedure:
124 mg of the title compound was obtained as a pale yellow solid by the same method as in Example 359 from 196 mg of the mixture of methyl 4-{4-[3-(5-methylsulfanylthiophen-2-yl)-imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate and ethyl 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl]benzoate obtained in the synthesis process in Example 375.