Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([N:21](CC)CC)C.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=[CH:34][C:35](Cl)=[O:36])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:21][C:35](=[O:36])[CH:34]=[CH:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1
Reactant: O=C(Cl)C=Cc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1NC(=O)C=Cc1cccnc1
Reaction time: 0.5 h

Procedure:
To a solution of the product of step 2 (0.7 g) and anhydrous triethylamine (0.7 ml) in dichloromethane (20 ml), 3-pyridin-3-ylacryloyl chloride hydrochloride (1.2 g) was added in batches in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. Then potassium carbonate solution (10%) was added. The mixture was extracted with EtOAc (20 ml*3). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to recover solvent. The residue was purified on silica gel column using EtOAc/petroleum ether/ethanol (2:1:5) as an eluent. The concentration of the eluent and crystallization provided a yellow solid powder.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[C:26](F)[CH:25]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=1.[CH2:32]([N:35]([CH2:49][CH2:50][CH3:51])[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[C:45](CC)[CH:46]=1)[C:41](O)=[O:42])=[O:37])[CH2:33][CH3:34]>>[CH2:23]([C@H:9]([NH:8][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH2:32][CH2:33][CH3:34])[CH2:49][CH2:50][CH3:51])=[O:37])[CH:39]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:2])[CH:15]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(C)c2)c1

Procedure:
Following the general procedure of EXAMPLE 452 and making non-critical variations and using (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol trifluoroacetate (VIII, EXAMPLE 5) and reacting it with (CH3—O—CH2—CH2—)2N—CO—CO—OH (IX) where the attachment to the -phenyl-ring is 1,3- for the carbonyl groups, the title compound is obtained, MH+=570.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 120 °C
Yield: 53.9 %

Procedure:
To a solution of N-tert-butyloxycarbonylpiperazine (5 g) in anhydrous dimethylformamide (75 ml) containing triethylamine (7.4 ml), was added 1-fluoro-4-nitrobenzene (3.81 g). The solution was heated at 120° C. for 5 h then the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous phase washed with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with ether and the resultant yellow solid filtered off. The solid was then chromatographed on silica gel, using a gradient elution of 0→1% methanol in dichloromethane to afford the title compound (4.45 g) as a yellow solid. 1H NMR (360 MHz, CDCl3) δ 1.49 (9H, s), 3.40-3.43 (4H, m), 3.59-3.62 (4H, m), 6.82 (2H, dd, J=9 and 1.8 Hz), 8.13 (2H, dd, J=9 and 1.8 Hz). MS (CI, NH3) 307 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].C[O:19][C:20](OC)([N:22]([CH3:24])[CH3:23])[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:21][C:20]([N:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(C)(OC)N(C)C
Reactant: COc1cccc(C2=CC(=O)CCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cccc(C2(CC(=O)N(C)C)CC=CCC2)c1

Procedure:
10 g of 3-(m-methoxyphenyl)-2-cyclohexen-1-ol obtained by reducing 3-(m-methoxyphenyl)-2-cyclohexen-1-one with sodium borohydride, are dissolved in 100 ml of xylene, whereupon 12 g of N,N-dimethylacetamide dimethyl acetal are added, and the mixture is boiled at reflux for 8 hours. After distillation of the solvent, the oil remaining behind is chromatographed on a 30-fold amount of silica gel. The fractions which are uniform in accordance with thin-layer chromatography and which are produced by elution with methylene chloride, are combined and evaporated, and there is obtained pure 1-(m-methoxyphenyl)-N,N-dimethyl-3-cyclohexene-1-acetamide in the form of a pale yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([OH:25])=O)[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:41](=[O:57])([O:43][CH2:44][CH:45]([NH2:56])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53])[NH2:42].Cl>CN(C=O)C>[C:41](=[O:57])([O:43][CH2:44][CH:45]([NH:56][C:23](=[O:25])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:53])[F:54])[NH2:42]
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: NC(=O)OCC(N)c1ccccc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A quantity of 30 mg (0.08 mmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (preparation according to WO2007/134862, Example 154A) was dissolved in 1 ml of DMF, and the solution was admixed with 21 mg (0.11 mmol) of EDC and with 15 mg (0.11 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. Then 23 mg (0.09 mmol) of the compound from Example 180A were added and the mixture was left with stirring at room temperature for 16 h. For work-up, 50 μl of 1N hydrochloric acid were added and the crude product was purified directly by preparative HPLC [Method 19]. This gave 34 mg (69% of theory) of the target compound.
Reaction SMILES: CO[NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[CH:6][C:5]=1[C:14](=[O:23])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:14](=[O:23])[C:5]3=[CH:6][NH:7][C:8]4[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=4[C:4]3=[N:3]2)=[CH:17][CH:18]=1
Reactant: CONc1c(C(=O)Nc2ccc(Cl)cc2)cnc2c1CCCC2
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cl
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 0.3 g of 4-(O-methylhydroxylamino)-3-(N-p-chlorophenylcarbamoyl)-5,6,7,8-tetrahydroquinoline and 15 mL of eutectic diphenyl ether-biphenyl is heated to 240° for 2 hours under nitrogen. It is cooled to room temperature, concentrated under high vacuum, and the residue is diluted with 100 mL of petroleum ether, and filtered. The collected solid is stirred with 15 mL of diethyl ether and 3 mL of 2N aqueous sodium hydroxide for 1 hour, filtered to remove insoluble material and the layers of filtrate are separated. The aqueous phase is treated with 0.3 g of ammonium chloride to give a yellow precipitate, which is collected and recrystallized from isopropanol containing hydrogen chloride to yield the 2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one hydrochloride.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=O)[CH2:7]C)=[CH:2]1.[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH2:16](Cl)Cl>C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:13][CH2:10][CH3:16])=[CH2:7])=[CH:2]1
Reactant: CCC(=O)c1ccoc1
Reactant: O=C([O-])[O-]
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Product: C=C(OCC)c1ccoc1
Yield: 29 %

Procedure:
To a stirring mixture of 1-(3-furyl)-1-propanone (6.75 g, 0.0612 mol) in 150 ml of methylene chloride was added TEOF (13.2 ml, 0.079 mol) with stirring followed by 100 mg of p-toluenesulfonic acid and the resulting mixture was stirred for 126 h. Potassium carbonate (2 g) was added to the above reaction mixture, stirred for 10 min, filtered, and concentrated in vacuo. The residue was distilled (35 mm, 82°-85° C.) to afford 2.5 g of (29%) 1-(3-furyl)-1-ethoxy-ethylene (Formula III: R2 =R3 =H;R4 =CH3CH2O;R5 =3-furanyl), as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([N:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[CH:26]=1>O1CCCC1.CN(C)C=O.O>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[CH:26][N:25]3[N:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Cn1cccc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a solution of 1-methyl-1H-pyrrole-2-carboxylic acid (121 mg, 0.970 mmol) in tetrahydrofuran (5 mL) were added oxalyl chloride (169 μL, 1.94 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol) was added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (56.0 mg, 14%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:34])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:34])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)N3CCCCC3)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCC(=O)N3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
(4-{[5-Nitro-2-(2-oxo-2-piperidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (36 mg, 0.07 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (1 mL) was added to the solution. The reaction mixture was stirred at room temperature for 16 h. The solution was treated with 3M Na2CO3 to pH 9 and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4 and then concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.3 CH2Cl2:MeOH:Et3N as an eluent to afford 27 mg of the title compound as a yellow solid (93%), m/z 392.6 [M+1]+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl>O1CCOCC1.[OH-].[Na+]>[CH:6]([OH:7])=[O:5].[NH:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:10][CH2:9]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCCNCC1)C3
Product: O=CO
Yield: 6.8 %

Procedure:
A solution of (S)-4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-azepane-1-carboxylic acid tert-butyl ester (180 mg; 1.11 mmol; 1 eq.) in a 4M solution of HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 16 hours. The residue was diluted with 0.1M NaOH and extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (38 mg, 7%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 7.37 (ddd, J=8.5, 6.8, 3.2 Hz, 1H), 7.12 (dd, J=11.7, 2.3 Hz, 1H), 6.88 (td, J=8.4, 2.3 Hz, 1H), 4.93-4.72 (m, 3H), 4.54 (d, J=15.1 Hz, 2H), 3.03-2.75 (m, 6.7H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.11-1.49 (m, 6.3H). HPLC (max plot) 90.3%, Rt 2.91 min. UPLC/MS: (MS+) 458.4 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=[CH2:23])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(Br)ccc(OCc3ccccc3)c2[nH]c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OCc2ccccc2)c2[nH]c(=O)c(C)cc12
Temperature: 100 °C

Procedure:
Palladium terakis(triphenylphosphine) (30 mg) is added to a solution of 8-benzyloxy-5-bromo-3-methyl-1H-quinolin-2-one (239 mg) and tributylvinyltin (203 μL) in toluene (7 mL) at room temperature. The reaction mixture is heated for 2 hours at 100° C., cooled to room temperature, evaporated and the product purified by flash column chromatography on silica gel, eluting with 2% ethyl acetate in dichloromethane.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O:18]O)(C)(C)C>ClCCl.O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CCCc2ccc(Br)cc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound 2, 1.1 g, 4.62 mmol) in 10 mL of dichloromethane was added chromium (VI) oxide (72 mg, 0.46 mmol) and 5 mL of tert-butyl hydroperoxide solution (TBHP). After stirring at room temperature for 8 h, the mixture was diluted with water (20 mL), extracted with diethyl ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (90:10 hexane/ethyl acetate) yielded the title compound (920 mg, 79% yield) as a white solid:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24]1[CH:33]=[C:32]([NH:34][C:35](=[O:51])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=3)[C:35]([NH:34][C:32]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:23][CH3:22])[CH:33]=3)=[O:51])[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(NC(=O)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1OC
Yield: 63.6 %

Procedure:
To a solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (155 mg, 0.48 mmol) and methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 0.44 mmol) in 10 mL of 1,4-dioxane and 1 mL of water was added Na2CO3 (140 mg, 1.32 mmol) followed by Pd(PPh3)4 (26 mg) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation. The residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=1:1) to give methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)-2-methoxybenzoate (160 mg, 64%) as solid. LC-MS: 572 [M+H]+, tR=1.62 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OCC1CCN(c2ncccn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of 4-piperidinemethanol (1.00 g) in dimethyl sulfoxide (28.9 mL), 2-chloropyrimidine (994 mg) and potassium carbonate (2.40 g) were added and the mixture was stirred at 100° C. for three hours. After cooling the reaction mixture to room temperature, water was added to it and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give [1-([pyrimidin-2-yl)piperidin-4-yl]methanol as a colorless oil (1.50 g).
Reaction SMILES: C(N(CC)CC)C.[CH:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=O)[CH2:15]2.FC(F)(F)CO[C:23](=O)[C:24]1[CH:29]=[CH:28][C:27](Cl)=[C:26](OC)[CH:25]=1.[CH2:36]1[CH2:40]OC[CH2:37]1>[Cl-].[Cl-].[Cl-].[Ti+3].[Zn]>[CH:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=[C:29]1[CH:28]3[CH2:27][CH:26]4[CH2:37][CH:36]([CH2:23][CH:24]1[CH2:25]4)[CH2:40]3)[CH2:15]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COc1cc(C(=O)OCC(F)(F)F)ccc1Cl
Reactant: C1CCOC1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCN(CC)CC
Product: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Reaction time: 0.25 h

Procedure:
Titanium trichloride, 7.9 g (51.3 mmol), was weighed into a round-bottomed flask in a glove bag under an argon atmosphere. Freshly distilled tetrahydrofuran (from LAH), 60 mL, was added quickly under argon flow. Care should be taken, as this addition can be exothermic. The purple suspension was stirred vigorously so as to break up the solid adhering to the walls of the flask. After 15 minutes, zinc dust, 5.2 g, was added all at once under argon with continued stirring. A moderate exotherm resulted in a reddish-brown mixture which did not contain black suspended solids. After 15 minutes stirring, the triethylamine, 11 mL, was added with exclusion of air. The mixture was then refluxed for 2 hours. A solution of 2-adamantanone, 3.0 g (20 mmol), and 2,2,2-trifluoroethyl-4-chloro-3-methoxybenzoate, 2.6 g (10 mmol) in dry THF, 30 mL, was added dropwise to the refluxing brown mixture over approximately 65 minutes. Reflux was continued overnight for 16 hours. The solvents were rotary evaporated from the cooled reaction mixture to yield a brown-black gum. This gum was triturated with hexanes, 100 mL, and ethyl acetate, 20 mL. The yellow-orange supernate was decanted and the trituration procedure was repeated. After 10 minutes of agitation, triethylamine and methanol, 5 mL each, were added. The gum began to stiffen and eventually became a lumpy solid. The solid was broken up and the supernate decanted. One final trituration was accomplished with 20% ethyl acetate-hexanes. The combined decanted supernates were rotary evaporated to a light yellow, semisolid paste. The mixture was treated with hot hexanes, 50 mL, and filtered warm to remove some insolubles. The residue obtained after rotary evaporation of the filtrate was applied to a 2.1×20 cm column of activity I aluminum oxide as a slurry in a small amount of warm hexanes. The column was eluted with hexanes to obtain adamantylidene adamantane. The elution was continued with 10% dichloromethane-hexanes to obtain an oil which contained two major mid Rf, UV-active components. The oil was taken up in a small amount of hot hexanes. A crystalline, colorless solid, weighing 0.71 g and having a melting point of 108°-112° C., precipitated out upon cooling.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1)[CH2:11][C:9]1[NH:8][CH:7]=[CH:6][N:10]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
The compound (130 mg) obtained in Example 3-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg) and the whole was stirred for 1 hour. After having been cooled to 0° C., the solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (16.4 mg) of the subject compound as a white solid.