Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH2:5][C:6](=[O:15])[C:7](=[N:13][OH:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:14][N:13]=[C:7]([C:6]1[O:15][CH2:2][CH2:3][S:4][CH:5]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NO)C(=O)CSCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NO)C1=CSCCO1
Yield: 92.1 %

Procedure:
Ethyl 4-(2-hydroxy-ethylthio)-2-hydroxyimino-3-oxo-butyrate (321 g.) is dissolved in boiling toluene (3.2 liters) and paratoluenesulphonic acid monohydrate (26 g.) is then added. Vigorous boiling results, with liberation of water, which is removed in a DEAN and STARK apparatus. The reaction mixture is heated under reflux for a further 15 minutes. After cooling, the toluene solution is filtered, and washed three times with water (a total of 1.5 liters), then with a saturated sodium bicarbonate solution (200 cc.) and finally with water (500 cc.). It is dried over magnesium sulphate, treated with decolourising charcoal, filtered and concentrated to dryness under reduced pressure (20 mm.Hg). Ethyl α-hydroxyimino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetate (273 g.) is obtained in the form of an oil which gradually solidifies.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
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: COCCOC
Product: Fc1ccc(-c2ccncc2)cc1-c1nc(-c2ccccn2)no1
Yield: 4.1 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmole), 4-pyridylboronic acid (76.7 mg,0.6265 mmol) and Pd(PPh3)4 (36.1 mg, 0.03123 mmol) in a solution of 2M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) was heated overnight at 105° C. Standard work up, afforded 4.1 mg (4%) of 3-(2-pyridyl)-5-[2-fluoro-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: C(OC([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O)C.[CH3:26][O:27][CH2:28][CH:29]1[CH2:33]O[C:31](=[O:34])[O:30]1>N1C=CC=CC=1>[CH3:26][O:27][CH2:28][CH:29]1[O:30][C:31](=[O:34])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:9][CH:8]=2)[CH2:33]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: c1ccncc1
Product: COCC1CN(c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)O1
Yield: 58 %

Procedure:
5.5 g (15.0 mmol) of t-butyl 4-(4-ethoxycarbonylamino-phenyl)-piperidine-1-carboxylate and 20 g (0.15 mol) of (RS)-4-(methoxymethyl)-1,3-dioxolan-2-one were stirred intensively in the presence of 2.37 g of pyridine for 18 hours at an oil bath temperature of 160°. After cooling the reaction mixture it was chromatographed on 840 g of silica gel 60 with ether. 3.4 g of t-butyl (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine-1-carboxylate were obtained as a yellowish oil. 1H-NMR (CDCl3) ppm: 7.48 (d,2H), 7.22 (d,2H), 4.76 (m,1H), 4.25 (bd,2H), 4.05 (t,1H), 3.92 (t,1H), 3.64 (d,2H), 3.43 (s,3H), 2.80 (t,2H), 2.64 (m,1H), 1.78 (bd,2H), 1.61 (m,2H), 1.49 (s,9H).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:32][CH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:39])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:32].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][C:34]3[CH:48]=[CH:47][C:37]([C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[O:39])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: CN1CCN(C(=O)c2ccc(CCl)cc2)CC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccc(C(=O)N6CCN(C)CC6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 13.2 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (406 mg), 1-(4-chloromethylbenzoyl)-4-methylpiperazine hydrochloride (1.119 g) and potassium carbonate (739 mg) in DMF (10 ml) was stirred at room temperature for 40 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: methanol =9:1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (86 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:27]1([CH2:36][C:37](O)=[O:38])[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:37](=[O:38])[CH2:36][N:27]1[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2Cl)s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2Cl)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2,4-dichlorophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.27 (s, 0.4H), 9.11 (brs, 1H), 8.28 (d, 0.6H), 8.27 (d, 0.4H), 8.00 (d, 0.6H), 7.98 (d, 0.4H), 7.72–7.68 (m, 1H), 7.33 (s, 0.6H), 7.25 (s, 0.4H), 4.66 (s, 1.2H), 4.48 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.06 (s, 1.2H), 3.57 (t, 1.2H), 3.45–3.39 (m, 2H), 3.26 (t, 0.8H), 1.75 (s, 3H), 1.25 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:30]1SC2C(C)=CC=CC=2N=1>>[CH3:30][C:3]1[C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=[CH:28][CH:2]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Cc1cccc2nc(Cl)sc12
Product: Cc1cccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-7-methyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.31 (m, 4H), 2.61 (s, 3H), 3.12 (q, J=11.8 Hz, 2H), 3.42 (d, J=12.8 Hz, 2H), 4.46-4.56 (m, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 8.43 (br. s., 2H), 8.52 (s, 1H). MS (ES+): m/z=391.16 [MH+]. HPLC: tR=2.24 min (ZQ2, polar—5 min).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:9][CH:8]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:46].[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@@H:49]([NH:55][C:56]([C:58]1[S:59][C:60]3[C:66](Br)=[CH:65][CH:64]=[CH:63][C:61]=3[CH:62]=1)=[O:57])[CH2:48]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:46].[N:47]12[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54]1)[C@@H:49]([NH:55][C:56]([C:58]1[S:59][C:60]3[C:66]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)=[O:14])=[CH:11][CH:12]=4)=[CH:65][CH:64]=[CH:63][C:61]=3[CH:62]=1)=[O:57])[CH2:48]2
Reactant: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)N1CCOCC1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(C(=O)N4CCOCC4)cc3)c2s1

Procedure:
164.7 mg (0.49 mmol) of 4-(4-morpholinylcarbonyl)phenyl trifluoromethane-sulphonate (Example 18A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.5 ml of DMF are reacted by general method D. An initial purification by preparative HPLC is followed by column chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 90:9:1). Drying under high vacuum results in 24.8 mg (13% of theory) of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]4[CH2:36][O:35][CH2:34]4)[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C>[OH:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([CH:33]4[CH2:36][O:35][CH2:34]4)[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C5COC5)CC4)nc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)nc(Nc2ccc(N3CCN(C4COC4)CC3)nc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
A mixture of 197f (200 mg, 0.30 mmol) and lithium hydroxide (70 mg, 3.0 mmol) in THF (9 mL), i-propanol (6 mL), and water (1 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and diluted with water (4 mL). It was then extracted with dichloromethane (2×10 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 197 (59 mg, 30%) as yellow solid. MS-ESI: [M+H]+ 638. 1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.70 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.14-8.11 (m, 1H), 7.59 (s, 1H), 7.55 (d, J=5.0 Hz, 1H), 6.82 (d, J=9.5 Hz, 1H), 6.58 (s, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.60-4.54 (m, 3H), 4.48-4.42 (m, 3H), 4.26-4.08 (m, 3H), 3.86 (d, J=12.0 Hz, 1H), 3.54 (s, 3H), 3.44-3.40 (m, overlap, 5H), 2.66-2.53 (m, 2H), 2.46-2.47 (m, 2H), 2.35-2.33 (m, 4H), 1.80-1.68 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([N:18]([C:21]1[N:26]=[N:25][C:24]([C:27]([O:29]CCCC)=[O:28])=[CH:23][CH:22]=1)[CH2:19][CH3:20])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([N:18]([C:21]1[N:26]=[N:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)[CH2:19][CH3:20])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)c1ccc(N(CC)C(C)c2cc(Br)ccc2OCc2ccccc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1ccc(C(=O)O)nn1)C(C)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
n-Butyl 6-[N-(1-(2-benzyloxy-5-bromophenyl)-eth-1-yl)-N-ethylamino]pyridazine-3-carboxylate (180mg) was dissolved in THF (5 mL) and methanol (5 mL) and sodium hydroxide solution added (0.61 mL, 2M). The mixture was stirred for one hour at ambient temperature, and then the solvents evaporated off. The resulting foam was dissolved in water (20 mL) and pH adjusted to pH 4-5 with glacial acetic acid. A white precipitate formed which was filtered off, washed with water and dried for 17 hours at 5° C. to give 6-[N-(1-(2-benzyloxy-5-bromophenyl)eth-1-yl)-N-ethylamino]pyridazine-3-carboxylic acid (134 mg, mp 129.2° C.).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@:27]([OH:42])([C@H:34]([S:36][CH:37]([CH2:40]O)[CH2:38][OH:39])[CH3:35])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@@:27]([OH:42])([CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)[C@H:34]([S:36][C@@H:37]1[CH2:38][O:39][C@@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[O:16])=[CH:9][CH:10]=2)[O:15][CH2:40]1)[CH3:35]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4′-fluoro-4-formylbenzanilide (300 mg, 1.2 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (385 mg, 1.1 mmol) and p-toluenesulfonic acid monohydrate (366 mg, 1.9 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (306 mg, yield 48%) as a colorless oil and the cis isomer (78 mg, yield 12%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [N:1]1C(Cl)=NC(Cl)=NC=1Cl.[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=O)=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1>CN(C)C=O>[C:27](/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)=[O:17])=[CH:20][CH:21]=1)#[N:1]
Reactant: O=C(O)/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#C/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Cyanuric chloride (727 mg, 3.94 mmol) was added to a dimethylformamide suspension of (E)-3-[4-[([1,1′-biphenyl]-4-ylcarbonyl)amino]phenyl]-2-propenic acid (900 mg, 2.63 mmol) obtained in Reference Example 74 at room temperature, which was stirred for 1 hour. After the solvent was distilled out under reduced pressure, the residue was dissolved in chloroform, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was stilled out under reduced pressure. The resulting residue was purified by silica gel column chromatography (development solvent; chloroform:ethyl acetate=20:1), to give the titled compound (561 mg) as a colorless powder from diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:15]3[CH2:16][CH2:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CO.O.C(O)C>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:15]3[CH2:16][CH2:17][NH:18][CH:19]([CH3:20])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc3n2CCN=C3C)cc1OC
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc3n2CCNC3C)cc1OC
Yield: 37 %

Procedure:
6-(3,4-Dimethoxyphenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.3 g) was dissolved in a mixture of 80 ml of methanol and 8 ml of water under argon. The solution was treated portionwise with 0.6 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.3 g of yellow-brown oil, was chromatographed on 60 g of silica gel with methylene chloride/methanol (49:1) as the eluent. The product, 0.9 g of yellow oil was dissolved in a 20-fold amount of ethanol, treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol, concentrated to 10 ml and treated with 40 ml of ethyl acetate. There was obtained 0.5 g (37%) of 6-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:0.6); m.pt.: 172°-175° C. (dec.). A sample was recrystallized from a 40-fold amount of ethanol and yielded the (2:1) fumarate; m.pt.: 178°-180° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1)=[O:14]
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Reactant: NC1CCN(CCc2ccccc2)CC1
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)NC1CCN(CCc2ccccc2)CC1
Yield: 47.4 %

Procedure:
A solution of 4.0 g of 5-fluoro-2-methylindole-3-carboxylic acid and 4.2 g of 4-amino-1-(2-phenylethyl)piperidine in 80 ml of tetrahydrofuran was allowed to stand for a while to precipitate a salt. To the suspension was added 4.7 g of dicyclohexylcarbodiimide and the mixture was stirred under reflux for 3 hours. After cooling, the precipitated dicyclohexylurea was filtered off and the filtrate was concentrated. The residue was crystallized by treatment of hexane. The crystals were filtered with suction and recrystallized from ethyl acetate to yield 3.7 g of 5-fluoro-2-methyl-N-[1-(2-phenylethyl)-4-piperidyl]indole-3-carboxamide, melting at 159°-162° C. The crude product (3.9 g) was recovered from the mother liquor.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:3]1.[Br-].[K+].Cl[O-].[Na+]>ClCCl.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH:10]=[O:11])[CH2:3]1
Reactant: CC1CCCC(CCCO)C1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1CCCC(CCC=O)C1
Temperature: 35 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
In a 2 L three-necked round-bottom flask equipped with a mechanical stirrer and a reflux condenser were introduced a solution of 3-(3-methylcyclohexyl)propan-1-ol (23.3 g, 0.15 mol) in dichloromethane (140 mL), a solution of potassium bromide (1.77 g, 15 mmol, 0.1 eq) in water (25 mL) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 300 mg, 1.92 mmol, 0.01 eq). To this mixture was added 0.35M aqueous sodium hypochlorite (594 mL). The mixture was stirred for 3 days at 35° C. then extracted with dichloromethane (500 mL). The organic layer was washed with water (300 mL), 1N HCl (300 mL) and brine (300 mL), dried over sodium sulphate and concentrated. The crude product was chromatographed on silica gel with 8% EtOAc in hexane as elution agent, followed by a bulb-to-bulb distillation (0.01 mBar, 79° C.) to give pure 3-(3-methylcyclohexyl)propanal (11.8 g, gc purity>98%; yield=51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)=[CH:15][C:14]=2[F:28])[CH2:11][C:10]([C:29]([C:35]([F:38])([F:37])[F:36])([C:31]([F:34])([F:33])[F:32])[OH:30])=[N:9]1.[CH3:39][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])([CH3:39])[CH3:26])=[CH:23][CH:24]=3)=[CH:15][C:14]=2[F:28])[CH2:11][C:10]([C:29]([C:35]([F:38])([F:37])[F:36])([C:31]([F:32])([F:33])[F:34])[OH:30])=[N:9]1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)cc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-(4′-acetyl-3-fluoro-biphenyl-4-yl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (10.0 mg, 0.02 mmol) prepared in Example 341 in tetrahydrofuran (1.0 mL), was slowly added methylmagnesium chloride (in 3.0 M tetrahydrofuran, 30.0 uL, 0.09 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 5 hours, quenched with a saturated solution of ammonium chloride at 0° C., and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH:30](C)C)[N:9]=3)[CH2:2]1.Cl[C:35]([C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])=[O:36].CCN(CC)CC>C1COCC1>[CH3:38][C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[C:35]([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)=[O:36]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (32 μL, 0.22 mmol) and NEt3 (29 μL, 0.22 mmol) in THF (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-7%) affording the title compound as a white foam (97 mg, 75%). LCMS (method A): RT 2.65 min [M+H]+ 575.3