Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[ClH:23].O1CCOCC1>O1CCOCC1>[ClH:23].[F:22][C:2]([F:1])([F:21])[C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)C1(C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 1-tert-butyl 4-ethyl 4-(trifluoromethyl)piperidine-1,4-dicarboxylate (0.15 g, 0.19 mmol) in 1,4-dioxane (10 mL) was added HCl-1,4-dioxane (4.0 M, 15 mL) solution and the mixture stirred at rt for 30 min. After completion of reaction (by TLC), solvent was evaporated to obtain brownish solid material (0.12 g) that was carried forward to the next step (i.e. synthesis of Compound 142) without purification. MS: 226.12 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:9]=1)(C)(C)C.[ClH:24]>CO>[ClH:24].[ClH:24].[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=2)[CH2:17][CH2:18]1
Reactant: CN1CCC(COc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCC(COc2cccc(N)c2)CC1
Temperature: 25 °C

Procedure:
[3-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester (1.6 g, 0.005 mol) is dissolved in 10 mL of methanol and treated with 10 mL 6 N HCl. The solution is stirred at rt over night and then heated for 4 h to 60° C. The solvent is removed under reduced pressure and the residue dried under vacuum to give a tan foam which is used without further purification. HPLC: 8.20 (System X2); [M+H]+ 221.0.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: BrCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,8-dibromooctane (4.41 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][NH2:18]>C1COCC1>[C:11]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]3[NH:17][NH:18][CH2:9][CH2:8][C:7]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCc1c(Cl)ncnc1-c1ccccc1
Reactant: NN
Solvent: C1CCOC1
Product: c1ccc(-c2ncnc3c2CCNN3)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 4-chloro-5-(2-chloroethyl)-6-phenylpyrimidine (150 mg) in dry THF (10 mL), hydrazine (5 mL, 1.0M in THF) was slowly added under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 60° C. for 5 hours and solvents were removed under reduced pressure. The resulting oil was purified by column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to afford 5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (45 mg) as colorless oily liquid. 1H NMR (DMSO-d6): δ 2.63-2.65 (t, 2H), 2.79-2.81 (t, 2H), 4.93-4.97 (t, 1H), 7.43-7.48 (m, 3H), 7.56-7.59 (m, 2H), 8.29 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([C:32]([OH:34])=[O:33])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd].C(O)(=O)C>[C:32]([OH:34])(=[O:33])[CH3:13].[C:25]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[C:32]([OH:34])=[O:33])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CNCCN1C(=O)N(c1ccccc1)c1ccccc1

Procedure:
A solution of 109 mg. (0.24 mmole) of (±)-4-(benzyloxycarbonyl)-1-(diphenylcarbamoyl)piperazine-2carboxylic acid (from Step A) in 3 ml of methanol containing 3 drops of acetic acid and 50 mg of 10% Pd/C was hydrogenated with rocking at 40 psi of hydrogen for 16 hours. The mixture was filtered through Celite and the solution was concentrated in vacuo to 66 mg (71%) of solid which was homogeneous by TLC (1:1:1:1 n-butyl alcohol-acetic acid-water-ethyl acetate, Rf =0.70). 1H NMR (CDCl3, 300 MHz, ppm): δ2.05 (s, 3H), 2.72 (m, 1H), 2.96 (m, 1H), 3.12 (m, 1H), 3.26 (m, 1H), 3.67 (m, 1H), 3.79 (m, 1H), 4.78 (br.s, 1H), 7.0-7.3 (m, 10H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)s1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Temperature: 78 °C
Yield: 64.7 %

Procedure:
5-Acetyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.245 g, 3.077 mmol) and ethyl formate (0.739 mL, 9.23 mmol) were dissolved in anhydrous ethanol (6.16 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (5.75 mL, 15.38 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.864 g, 1.99 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[O:28][C:29](=[O:32])[NH:30][N:31]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[O:28][C:29](=[O:32])[NH:30][N:31]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (91 mg, 0.198 mmol) in MeOH (2 mL) is added aqueous 1N NaOH (4 mL, 4 mmol). After stirring at room temperature for 2 hours, the crude is quenched with 1N HCl and concentrated under reduced pressure to remove MeOH and is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (2R,4S)-5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoic acid (62 mg). HPLC retention time=1.60 minutes (condition B); MS (m+1)=430.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.12 (d, J=7.1 Hz, 3H) 1.60 (ddd, J=13.8, 9.9, 4.3 Hz, 1H) 1.85 (ddd, J=13.6, 9.6, 4.0 Hz, 1H) 2.35-2.47 (m, 1H) 2.79 (dd, J=13.7, 7.8 Hz, 1H) 2.86 (dd, J=13.7, 7.8 Hz, 1H) 4.11-4.28 (m, 1H) 7.28 (d, J=8.3 Hz, 2H) 7.35-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.57-7.65 (m, 3H) 7.70 (t, J=1.8 Hz, 1H) 8.84 (d, J=8.8 Hz, 1H) 12.05 (br. s., 1H) 12.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:18])([F:19])/[CH:16]=[CH:17]/[C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: Fc1ccc(I)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-fluoro-4-iodo-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]3[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=1)[N:6]=[CH:5]2.FC(F)(F)C(O)=O>ClCCl>[OH:25][CH2:24][C:23]([NH:22][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)[CH:5]=[N:6]3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Yield: 62.2 %

Procedure:
2-(5-Chloro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (124 mg, 241 μmol) was dissolved in dichloromethane (3 mL) then trifluoroacetic acid (1 mL) added. After 15 h the mixture was concentrated in vacuo and Jan. 10, 1960 ammonium hydroxide/methanol/dichloromethane solution (25 mL) added. After 1 h the mixture was concentrated in vacuo and purified by chromatography (silica, 24 g Analogix column, 0-4% of methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-(5-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)amide (57.7 mg, 62%) as a solid. MS (M+H)+=385; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.70 (d, J=9.0 Hz, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.60 (d, J=2.1 Hz, 1H), 3.59 (d, J=5.7 Hz, 2H), 1.44 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]1=[O:17])[CH3:26]
Reactant: CCI
Reactant: O=c1[nH]cc(-c2ccccc2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a solution of 8-phenyl-1,6-naphthyridin-5-one (142 mg, 0.6 moles) in 5 ml DMF was added solid potassium carbonate. The resulting suspension was stirred under nitrogen at 21° C. for 30 minutes. Iodoethane (0.13 ml, 1.6 moles) was added and the reaction mixture heated overnight to 80° C. The mixture was cooled and concentrated under vacuum, and chromatographed by silica gel [column chromatography, eluting with 1:1 ethyl acetate/hexanes] to give 70 mg (47% yield) of the desired 6-ethyl-8-phenyl-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 141.5°-141.7° C.; 1H NMR (CDCl3, 300 MHz) δ1.44 (t, 3H, J=7.2 Hz), 4.12 (q, 2H, J=7.2 Hz) , 7.38-7.63 (m, 7H), 8.78 (dd, 1H, J=8.1, 2.0 Hz), 8.95 (dd, 1 H, J=4.6, 1.8 Hz); 13C NMR (75 MHz, CDCl3) δ161.59, 154.09, 151.99, 136.51, 135.38, 134.01, 129.98, 128.38, 127.66, 121.96, 121.74, 120.98, 44.52, 14.67; IR (KBr) vmax 1647, 1620, 1597, 1587, 1550, 1498, 1437, 1375, 1298, 1246, 1178, 1169, 792, 758, 726, 694, 626, 598, 499, 455 cm-1 ; mass spectrum (EI), m/e 250. Anal. (C16H14N2O) Calcd.: C, 76.78; H, 5.64; N, 11.19. Found C, 76.78; H, 5.61; N, 11.18.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][CH:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][OH:27]>CN(C)C=O>[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:24][CH2:25][CH2:26][OH:27])[CH:7]=1)([OH:3])=[O:5]
Reactant: OCCCCl
Reactant: CCOC(=O)c1c[nH]c(=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CCCO)c(=O)c2ccccc12
Temperature: 100 °C

Procedure:
A mixture of 21.6 g of 4-ethoxycarbonyl-1(2H)-isoquinolone, 25 g of anhydrous potassium carbonate and 100 ml of dimethylformamide was heated at 100° C. for 2 hours. Then, 14 ml of 3-chloropropanol was added thereto and the mixture was heated at 110° C. for 4 hours. The solvent was distilled off and the residue was extracted with dichloromethane. The extract was washed with water, dried and the solvent was distilled off. 120 ml of an ethanolic solution of 5.5 g of potassium hydroxide was added to the residue, and the mixture was warmed. After cooling, the reaction mixture was poured into ice-water and then filtered. The filtrate was rendered neutral with dilute acetic acid, and the precipitated crystals were filtered and recrystallized from a mixture of ethanol and petroleum ether to obtain 12.5 g of 4-carboxy-2-(3-hydroxypropyl)-1(2H)-isoquinolone having a melting point of 205° C. as colorless prisms.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:30]2[CH:31]=[C:32]([C:36]3[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:38](=[O:39])[CH2:37][C:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:31]=1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 52.2 %

Procedure:
Prepared from [2-amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G34) (245 mg, 0.75 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (300 mg, 1.1 mmol) according to the general procedure K. Obtained as a yellow-brown foam (211 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[S:12])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([N:13]=[CH:17][N:18]([CH3:20])[CH3:19])=[S:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)NCCNC(=O)OC(C)(C)C
Yield: 51 %

Procedure:
The title compound was synthesised from (2-Thioureido-ethyl)-carbamic acid tert-butyl ester and Dimethylformamide dimethyl acetal according to the procedure described for Example C in 51% yield. MS (m/e): 275.4 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH3:8])[C:3]=1[CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:35]=[CH:36][C:37]([C:2]4[CH:6]=[N:5][N:4]([CH2:7][CH3:8])[C:3]=4[CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:38][CH:39]=3)=[CH:32][CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCn1ncc(Br)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(CC)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(4-bromo-2-ethyl-2H-pyrazol-3-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH2:19]=O>C(O)=O>[CH3:19][NH:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[O:8][C:4]=2[CH:3]=1
Reactant: CN1CCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Reactant: C=O
Solvent: O=CO
Product: CNc1cc2oc(N3CCN(C)CC3)nc2cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 50 mg portion of 6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 5 ml of formic acid, and the solution was mixed with 3 ml of formaldehyde and stirred at room temperature for 3 hours. The solvent was concentrated under a reduced pressure, and the resulting oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (chloroform:methanol=20:1) to obtain the title compound (28 mg) in light yellow color.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4].[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:16]([O:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][CH2:6][C:2]([CH3:15])([CH3:1])[C:3]([OH:5])=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CCCC(C)(C)C(=O)O)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(CCCC(C)(C)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 35.5 %

Procedure:
At room temperature, 34 mg of p-toluenesulfonic acid was added to a mixture of 4.33 g of 2,2,6,6-tetramethylpimelic acid (mfd. by Tokyo Kasei (TCI), Japan), 4.24 g of benzyl alcohol and 16 ml of toluene. By equipping with a Dean-Stark type dehydration tube, this was stirred for 60Hours while heating under reflux, and then cooled down to room temperature. The insoluble matter was removed by filtration, the filtrate was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (methanol-chloroform) to obtain 2.18 g of 7-(benzyloxy)-2,2,6,6-tetramethyl-7-oxoheptanoic acid as a colorless oily substance. FP: 307.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)=O)[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9]>C(#N)C.P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9])[CH2:11][CH:12]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1
Reactant: COc1c(Br)cc(CC(=O)NCCc2cccc(NS(C)(=O)=O)c2)cc1Br
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1c(Br)cc(CC2NCCc3cc(NS(C)(=O)=O)ccc32)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 2-(3,5-dibromo-4-methoxy-phenyl)-N-[2-(3-methanesulfonylamino-phenyl)-ethyl]-acetamide in 15 mL of acetonitrile, phosphorus oxychloride is added. The reaction mixture is refluxed for 5 h. The residue after concentration is evaporated 3 times with MeOH, dissolved in 20 mL of MeOH, cooled with an ice bath, and NaBH4 is added by small portions. The reaction mixture is stirred overnight at room temperature, concentrated, dissolved in chloroform, washed with 1N NaOH, dried over Na2SO4, filtered, and concentrated. The residue is dissolved in methanol, and a solution of (COOH)2.2H2O in methanol is added.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=1)[O:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]2[CH2:27][CH:26](S(C)(=O)=O)[CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(#N)C>[CH:23]([N:24]1[CH2:27][CH:26]([N:2]([C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[O:5][CH3:6])[CH3:1])[CH2:25]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CNc1ccccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N(C)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 25.9 %

Procedure:
To a solution of 0.65 g of N-methyl o-anisidine in 15 mL of acetonitrile, was added 0.280 g of K2CO3, followed by 0.650 g of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction mixture was heated at 80° C. for 1 h then at 50° C. overnight. Water was added and the mixture was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The product was filtered through 100 mL of silica gel, eluting a with 15% ethyl acetate/hexanes then 25% ethyl acetate/hexanes to give 0.200 g of the desired product: mp 91-95° C. MS (ES) m/z (relative intensity): 356 (M++H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.NN>CO.[Ni]>[CH3:1][NH:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CNc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CNc1ccc2cccnc2c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a solution of N-methyl-8-nitroquinolin-7-amine (1.6 g, 7.9 mmol) in MeOH (25 mL) was added hydrazine hydrate (2.25 g, 455 mmol) and Raney Ni (8 drops). The mixture was stirred at room temperature for 20 minutes. The catalyst was removed by filtration and the filtrate was concentrated to give N7-methylquinoline-7,8-diamine as a yellow solid (1.2 g, yield 80%). ESI MS: m/z 174 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:1][C:2]1[O:6][C:5]([C:7]2[O:8][CH:14]=[C:12]([CH2:11][Cl:10])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Cl)o1
Product: ClCc1coc(-c2ccc(Cl)o2)n1
Yield: 24 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-chloro-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-chloro-2-furyl)-4-chloromethyloxazole. The yield was 24%. Recrystallization from diethyl ether-hexane gave colorless prisms, mp 107-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:17].[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccccc1F
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1F
Yield: 4.8 %

Procedure:
A mixture of 2-amino-3-(2-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.36 g), m.p. 160°-165° C.