Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12]C=C[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18]1[CH2:22][O:21]C[CH2:19]1.C[Li]>C(OCC)C.O>[CH2:1]([N:8]1[CH2:12][CH:18]([CH3:19])[CH:22]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC1CN(Cc2ccccc2)CC1O
Yield: 75.8 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, and 60.0 g of THF in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500W Xe lamps (UXL-500D xenon lamp produced by Ushio). 300 mL (0.30 mol) of 1 mol/L methyllithium (MeLi) in diethyl ether solution (produced by Kanto Chemical Co., Inc.) was continuously added to the reaction mixture and stirred for 5 hours at about 5° C. using an ice-bath. After completion, water was added to destroy excess MeLi at about 5° C. using an ice-bath. Acetone and diethyl ether were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 14.5 g of 1-benzyl-4-methyl-3-pyrrolidinol (yield 76.0%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:15]([N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([OH:48])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:49][CH2:50][C:51]1([CH2:56]OS(C(F)(F)F)(=O)=O)[CH2:55][CH2:54][CH2:53][CH2:52]1>>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:15]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:56][C:51]2([CH2:50][F:49])[CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)OCC1C(OCc1ccccc1)C(Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(=O)(OCC1(CF)CCCC1)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@H](OCC2(CF)CCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Beginning with (R)-5-[1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-hydroxymorpholine-4-carboxylic acid tert-butyl ester and trifluoromethane-sulfonic acid 1-fluoromethyl-cyclopentylmethyl ester, the desired compound may be prepared essentially as described in Preparation 306.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21]
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Temperature: 0 °C
Yield: 90.4 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with CH3I (0.68g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at 27° C. for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-methyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6a, 1.10 g, 91%). Nitro compound (6a, 1.21 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 960 mg, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylamino propyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7b, 0.27 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8b, 351 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19]3)[CH2:15][CH2:14]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH3:1][C:2]1[N:3]([S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:4]2[C:9]([C:10]=1[C:11]([N:13]1[CH2:14][CH2:15][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19]3)[CH2:17][CH2:18]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1[nH]c2ccccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a stirred solution of 40 mg (0.11 mmol) of 1′-[(2-methyl-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which has been described in example 43) in 3 ml DMF was added 5 mg (0.11 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 24 mg (0.14 mmol) of benzenesulfonyl chloride was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Re-crystallization in Et2O afforded 45 mg (80%) of 1′-{[2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidine] as white crystals. ES-MS m/e (%): 487.4 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][CH:9]=1.Cl.[CH2:20]([NH2:22])[CH3:21].O>C(Cl)Cl>[CH2:20]([NH:22][C:15](=[O:17])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([Br:7])=[CH:13][CH:12]=1)[CH3:18])[CH3:21]
Reactant: CCN
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)C(C)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
16.6 g (130 mmol) oxalyl chloride are added to 15.0 g (65 mmol) 2-(4-bromo-phenyl)-propionic acid (Bioorg. Med. Chem. Lett. 2010, 20, 887) in 75 mL DCM at 0° C. The cooling is removed and the mixture is stirred for 2 h under reflux. After that time, the solvent is evaporated and the residue is taken up in 70 mL THF. 3.20 g (39 mmol) ethylamine hydrochloride and 66.0 g (655 mmol) TEA are added and the mixture is stirred for 16 h at rt. After that time, iced water is added, the mixture is extracted with EtOAc and the organic layer is dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Br:19][C:20]1[C:21]([F:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([F:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1c(F)ccc(Br)c1F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1c(F)ccc(Br)c1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-2, 6-difluorobenzaldehyde 40 (81.4 mg, 0.607 mmol) and subsequently PTSA (230.9 mg, 1.214 mmol) was added, and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 41. The crude 41 was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(3-bromo-2,6-difluorobenzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 41 was eluted at 32% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH:15]=[C:14]([C:27]([O:29]C)=[O:28])[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:32]O>[OH-].[Na+].O>[CH3:32][C:13]1[C:14]([C:27]([OH:29])=[O:28])=[CH:15][C:16]([C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[CH:17][C:12]=1[C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:31])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=1
Reactant: CO
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)c(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylate (XXXVIII, step 2, 555 mg, 1.24 mmol) in methanol (6 mL) and sodium hydroxide (2 mL of a 6.0 M mixture in water, 12 mmol) is stirred at 20-25 degrees C. for 4 hours. The reaction mixture is partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous phase is acidified to pH=4 with hydrochloric acid (1N), extracted with ether (3×100 mL), and the combined organic phases are concentrated under reduced pressure to give methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylic acid (IX-XXXIX), NMR (300 MHz, CDCl3) □ 8.37, 8.12, 7.89, 7.80, 3.51, 3.22, 2.76, 1.74, 1.59, 1.02 and 0.79.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:9][C:8](=[O:10])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cccnc2c(=O)o1

Procedure:
Imidazo[4,5-c][1,5]naphthyridine-2,4-diamines of the invention can be prepared according to Reaction Scheme V, wherein D, R, R1, R4a, Ph, m, and p are as defined above. 3-Aminopyridine-2-carboxylic acids of Formula XXXIII are known and can be prepared by known methods. The compound where n and m are both 0 is commercially available. In step (1) of Reaction Scheme V, a 3-aminopyridine-2-carboxylic acid of Formula III is heated with acetic anhydride to provide a 2-methyl-4H-pyrido[3,2-d][1,3]oxazin-4-one of Formula XXXIV.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2F)CC1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a stirred solution of 2,5-difluorophenol (1.0 g, 0.0076 mole) in DMF (20 mL) was added cesium carbonate (12.4 g, 0.038 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 0.076 mole). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (10% ethyl acetate in hexane) to afford 1.5 g (63.0%) of 4-(2,5-Difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 85%. 1H NMR (CDCl3): δ 7.0 (m, 1H), 6.6 (m, 1H), 6.5 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.4 (m, 4H), 2 (m, 2H), 1.9 (m, 2H). 1.5 (s, 9H). A solution of 4-(2,5-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.0047 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 1 hour. Ether was then added, and the resulting precipitate was isolated by filtration and dried to afford 0.65 g (65%) of 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride. LCMS: 214.1 (M+1)+, 100%. 1H NMR (CDCl3): δ 9.2 (bs, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.2 (m, 2), 3.0 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H).
Reaction SMILES: FC1C(O[C:9](=[O:31])[NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[S:18][C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[C:20]([C:22]#[N:23])[N:21]=3)[CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH2:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][NH:37]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:22]([C:20]1[N:21]=[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:9]([N:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:36]3)=[O:31])[CH2:12]2)[S:18][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[N:23]
Reactant: N#Cc1nc(N2CCC[C@@H](NC(=O)Oc3c(F)c(F)c(F)c(F)c3F)C2)sc1Nc1ccccn1
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(N2CCC[C@@H](NC(=O)N3Cc4ccccc4C3)C2)sc1Nc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of crude {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid pentafluorophenyl ester (˜50 μmol) in tetrahydrofuran (1 mL) was cooled to 0° C. under an atmosphere of argon and isoindoline (12.6 mg, 106 μmol) and diisopropylethylamine (20 μL, 115 μmol) were added. The reaction mixture was stirred at 0° C. for 1 hour then warmed to ambient temperature and stirred for an additional hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL), poured into water (10 mL) and extracted with ethyl acetate (4×5 mL). The combined organic extracts were washed with brine (2×5 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography using a 12 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo to a yellow solid. The yellow solid was taken up in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a yellow viscous oil (11.3 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>CO>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: Nc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-5-bromo-3-nitro-benzoic acid (5 g, 19.15 mmol) in methanol (100 mL) was added a saturated ethereal solution of diazomethane gas (75 mL) until the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (5 g, 94.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([NH:17][NH2:18])=[O:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:19](OCC)(OCC)OCC.CS(O)(=O)=O>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:16][CH:19]=[N:18][N:17]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)/C=C\n1cnc(-c2cccc(Cl)c2)n1
Reactant: CCOC(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1cccc(-c2ncn(/C=C\c3nnco3)n2)c1
Temperature: 80 °C
Yield: 24.1 %

Procedure:
In a 3-neck 25 mL round-bottomed flask, (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.180 g, 1.0 eq.), triethyl orthoformate (0.2006 g, 1.9 eq.) and Methane sulphonic acid (0.009 g, 0.1 eq.) was mixed. Reaction was carried out under N2 atmosphere. Reaction mixture was refluxed at 80° C. for 1 h. Completion of the reaction was monitored on TLC using ethyl acetate:n-hexane (1:1) as mobile phase. The resulting reaction mass was poured in ice-water slurry (50 mL) and extracted with ethylacetate (3×20 mL). Organic layer was washed with brine solution followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 0.150 g of crude compound which was further purified using column chromatography to afford 0.045 g pure compound (Yield 24.2%): 1H NMR (400 MHz, CDCl3) δ 10.21 (S, 1H), 8.5 (S, 1H), 8.18 (S, 1H), 8.05-8.06 (t, 1H), 7.50-7.53 (d, J=10.8 Hz, 1H), 7.40-7.43 (t, 1H), 6.25-6.27 (d, J=11.2 Hz, 1H): LCMS for C12H8ClN5O [M+1]+ 273.68 found 273.80 at 3.336 min.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
Formaldehyde (37% in H2O; 15.6 μL, 0.210 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (25 mg, 0.053 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.111 g, 0.525 mmol) was then added in one portion to the reaction mixture. The reaction was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and saturated aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure yield a white solid. The solid was suspended in DCM (2 mL) and cyclohexane (10 mL) then filtered to afford the title compound (16) (19 mg, 73%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.70-7.61 (m, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.14-2.97 (m, 4H), 2.88 (d, J=10.6 Hz, 2H), 2.46-2.36 (m, 1H), 2.22 (s, 3H), 2.07-1.93 (m, 2H), 1.78-1.58 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1OC(C)=O
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
A solution of 4-acetoxy-3-methoxynitrobenzene (8.5 g, 40 mmol) in ethanol (175 ml) containing 10% palladium-on-charcoal catalyst (50% in water, 0.5 g) was stirred under hydrogen at atmospheric pressure for 1.5 hours. The catalyst was removed by filtration and the volatiles were removed by evaporation to give 4-acetoxy-3-methoxyaniline as an oil (6.92 g, 95%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[CH2:16]2)=[CH:11][CH:10]=1.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>O>[CH2:44]([O:43][C:41]([CH2:40][CH2:39][CH2:38][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:16][C:17]3[C:22](=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[C:19]([O:28][CH3:29])[C:18]=3[O:30][CH3:31])[CH2:23]2)=[CH:13][CH:14]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)C1(c2ccc(O)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
Sodium hydride (60% oily, 9.8 mg, 0.244 mmols) was added to a DMF (2 ml) solution of ethyl 2-(4-hydroxyphenyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (81.5 mg, 0.203 mmols), with cooling with ice. The reaction mixture was stirred at room temperature for 30 minutes, and ethyl 4-bromobutyrate (0.0600 ml, 0.406 mmols) was dropwise added thereto at room temperature, and stirring was continued for 3 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain the entitled compound (85.1 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: C1COCCN1
Product: N#Cc1c(N2CCOCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 448 mg (5.14 mmol) of morpholine to give 109 mg (63% of theory) of the title compound.