Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:11]=[CH:12][C:13](OC)=[O:14].Cl>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:11]=[CH:12][C:13]([NH:2][OH:3])=[O:14]
Reactant: NO
Reactant: COC(=O)C=Cc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)NO)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A solution of hydroxylamine hydrochloride (5.09 g, 72 mmol) in methanol (26 ml) was added to a solution of 88% potassium hydroxide (6.99 g, 109 mmol) in methanol (15.3 ml), keeping the temperature below 40° C. The mixture was cooled to 0° C., filtered, and methyl 3,4-dimethoxycinnamate (8.0 g, 36 mmol) was added to the filtrate. After two hours, concentrated HCl (5 ml) was added to the cold solution. The resulting precipitate was filtered, washed with water and ether, and dried in vacuo, to give 6.74 g (84% yield) of the named compound, mp 183°-185° C.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: N#Cc1ccc(Nc2ccccn2)c([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 45.9 %

Procedure:
A mixture of 4-cyano-2-nitroaniline (10.8 g, 66 mmol), 2-bromopyridine (12.6 g, 80 mmol), anhydrous potassium carbonate (9.12 g, 66 mmol) and copper-bronze (1.0 g, 15.7 mmol) in nitrobenzene (100 ml) was heated overnight at 200° C. The reaction mixture was cooled and filtered through a pad of celite. The filter cake was washed with dichloromethane (500 ml) and the filtrate was evaporated. The resultant residue was purified by column chromatography (silica gel, 500 g; n-hexane/ethyl acetate/dichloromethane (4/1/1)) to afford 7.28 g (46%) of 4-cyano-2-nitro-N-(2-pyridyl)aniline as orange solids.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=O.[Cl-].[OH:27][NH3+:28].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=[N:28][OH:27]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 25.2 %

Procedure:
32 g (89.3 mmol) of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone are dissolved in 200 ml of ethanol. To the solution are added 7.4 g (107 mmol) of hydroxylammonium chloride and 21.2 g (268 mmol) of pyridine. The reaction mixture is refluxed for 1.5 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 8.4 g of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone oxime as a white solid with a melting point of 70-72° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.89 (t, 3H), 1.20-1.40 (m, 16H), 1.40-1.50 (m, 2H), 1.79 (m, 2H), 3.86-4.03 (m, 2H), 6.93(E)/6.97(Z) (d, 2H), 7.44(E)/7.53(Z) (d, 2H), 8.59(Z)/8.61 (E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=1:4.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.F[C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][CH:12]=[CH:13][CH:14]=3)[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1ccnn1
Yield: 44 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 10, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (75.2 mg, 44%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 7.74 (d, 2H), 7.42-7.17 (m, 7H), 7.03-6.83 (m, 6H), 5.28 (d, 1H), 5.12 (d, 1H), 4.73 (d, 1H), 3.71-64 (m, 1H), 3.31-3.22 (m, 1H), 3.006-2.93 (m, 1H), 2.89 (dd, 1H), 2.71-2.64 (m, 1H), 2.52 (dd, 1H), 1.79-1.70 (m, 1H). MS (EI) for C28H27FN5O3 found 500 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[S:5])[CH3:2].I[CH3:16]>CO>[CH3:16][S:5][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CI
Reactant: CCNC(=S)N1CC2(C=N1)CCCC2
Solvent: CO
Product: CCN=C(SC)N1CC2(C=N1)CCCC2
Temperature: 45 °C
Yield: 0.3 %

Procedure:
0.55 g (1 mol equiv.) 2,3-Diazaspiro[4.4]non-3-ene-2-carbothioic acid ethylamide was dissolved in 15 mL MeOH, 3.4 mL (21 mol equiv.) iodomethane was added and the magnetically stirred reaction mixture was heated at 45° C. for 2 hours. Volatiles were removed in vacuo. The residue was taken up in dichloromethane (DCM) and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to give 0.57 g (97%) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.3 Hz, 3H), 1.64-1.80 (m, 8H), 2.46 (s, 3H), 3.54 (q, J=7.3 Hz, 2H), 3.57 (s, 2H), 6.72 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[S:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].O.[C:28](=O)(O)[O-].[Na+].IC>C(O)C>[CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18]([S:24][CH3:28])=[N:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C([O-])O
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=S
Agent: [Na+]
Solvent: CCO
Solvent: CI
Solvent: O
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)nc1SC
Reaction time: 24 h

Procedure:
The product of step (iii) (0.58 g) was dissolved in ethanol (30 ml) and water (5 ml) and treated with sodium bicarbonate(0.14 g) and iodomethane (0.2 ml) and stirred for 24 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4) and solvent evaporated under reduced pressure. The residue was triturated with isohexane and filtered to give the product. Yield 0.41 g.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[NH2:12][CH2:13][CH2:14][OH:15].CO>ClCCl>[OH:15][CH2:14][CH2:13][NH:12][CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: NCCO
Reactant: C[Si](C)(C)C#CC[C@H](O)CCl
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)C#CC[C@H](O)CNCCO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2S)-1-chloro-5-(trimethylsilyl)pent-4-yn-2-ol (80 g, 420 mmol) and 2-aminoethanol (110 g, 1.8 mol) was stirred at 80° C. for 18 hours. Silica gel chromatography (Gradient: 1% to 10% methanol in dichloromethane) provided the product as a yellow oil. Yield: 30 g, 140 mmol, 33%. 1H NMR (400 MHz, CD3OD) δ 3.80-3.88 (m, 1H), 3.61-3.72 (m, 2H), 2.84 (dd, J=12.3, 3.3 Hz, 1H), 2.69-2.81 (m, 2H), 2.64 (dd, J=12.0, 8.5 Hz, 1H), 2.45 (dd, half of ABX pattern, J=16.6, 5.5 Hz, 1H), 2.37 (dd, half of ABX pattern, J=16.6, 7.0 Hz, 1H), 0.12 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:13])[F:14])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 80 °C

Procedure:
Ethyl 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylate (6C) (58 g, 0.2 mol, crude reaction slurry containing Pd/C) was suspended in NaOH (814 mL of 5 M, 4.1 mol) in a 1 L flask with a reflux condenser and heated at 80° C. for 18 h, followed by further heating at 100° C. for 5 h. The reaction was filtered warm through packed Celite to remove Pd/C and the Celite was rinsed with 1 N NaOH. The filtrate was acidified to about pH 1 to obtain a thick, white precipitate. The precipitate was filtered then rinsed with water and cold acetonitrile. The solid was then dried under vacuum to provide 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (2) as a white solid. 1H NMR (400.0 MHz, DMSO-d6) δ 15.26 (s, 1H), 13.66 (s, 1H), 8.98 (s, 1H), 8.13 (dd, J=1.6, 7.8 Hz, 1H), 8.06-7.99 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29]CC)=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([OH:29])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Yield: 95.1 %

Procedure:
Ethyl 2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (1.0 g) obtained in Example 1 was dissolved in tetrahydrofuran (10 ml) and ethyl alcohol (10 ml), and 4N sodium hydroxide (10 ml) was added. The mixture was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 6N hydrochloric acid and the precipitated crystals were collected by filtration to give the title compound (0.9 g, yield 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([N+:25]([O-])=O)=[CH:11][C:12]([CH3:24])=[C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)=[CH:4][CH:3]=1.OC1C=CC(SC2C([N+]([O-])=O)=CC(C)=C(NC(=O)CC3C=CC=CC=3)C=2)=CC=1>>[NH2:25][C:10]1[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][C:13]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)cc1NC(=O)c1ccccc1
Agent: Cc1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)cc1NC(=O)Cc1ccccc1
Product: Cc1cc(N)c(Sc2ccc(O)cc2)cc1NC(=O)c1ccccc1
Yield: 100 %

Procedure:
The product from Example 267B was reacted according to the procedure from Example 265C substituting the product from Example 267B for the product from Example 265B to provide the title compound as a brown solid (0.11 g, 100%). This material was utilized without purification by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8](O)([CH2:28][O:29]S(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([O:29][CH2:28]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@@]1(c2ccccc2F)CO1
Temperature: 40 °C
Yield: 72.2 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (100 mg) was dissolved in dimethylformamide (4 ml), to which potassium carbonate (42 mg) was added, and the mixture was heated at 40° C. for 1 hour. The resultant was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and a saturated aqueous solution of sodium chloride (10 ml) successively. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/4). The desired fraction was concentrated and the residue was recrystallized from diisopropyl ether to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (58 mg) as a colorless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7](=[O:15])[CH2:8]P(=O)(OC)OC.[Li+].[Cl-].CCN([CH2:26][CH3:27])CC.[NH4+].[Cl-].[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>C(Cl)Cl.C1COCC1>[C:30]([O:33][C@@H:34]1[CH2:35][C@@H:34]2[O:33][C:30](=[O:32])[CH2:31][C@@H:35]2[C@H:26]1/[CH:27]=[CH:8]/[C:7](=[O:15])[CH2:6][O:5][C:4]1[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[CH:3]=1)(=[O:32])[C:31]1[CH:4]=[CH:3][CH:2]=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Reactant: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1cccc(Cl)c1
Reaction time: 1 h
Yield: 72 %

Procedure:
Phosphonate 11 (20.5 g, 70.0 mmol), 2.6 g (62 mmol) of LiCl, and 200 mL of THF were mixed together at 0° C. and 6.10 g (60.4 mmol) of NEt3 was added. Aldehyde 12 (14.0 g, 51.1 mmol) dissolved in 50 mL of CH2Cl2 was then added dropwise. After 1 h, the reaction was poured into 200 mL of a 1/1 mixture of saturated NH4Cl/ethyl acetate, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). Combined organic layers were dried over MgSO4, filtered, concentrated, and the residue was chromatographed on silica gel eluting with ethyl acetate/hexanes, 3/2, to afford 16.2 g (72%) of 13 as a white crystalline solid, m.p.=101.0-102.0° C. 1H NMR δ 8.0-7.9 (m, 2 H), 7.62-7.52 (m, 1 H), 7.50-7.38 (m, 2 H), 7.18 (t, J=8.2 Hz, 1 H), 7.0-6.82 (m, 3 H), 6.75-6.70 (m, 1 H), 6.54 (d, J=15.1 Hz, 1 H), 5.32 (q, J=6.2 Hz, 1 H), 5.12-5.05 (m, 1 H), 4.66 (s, 2 H), 3.0-2.8 (m, 3 H), 2.7-2.2 (m, 3 H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[I:19]Cl.O>C(O)(=O)C>[I:19][C:10]1[C:11]([NH2:13])=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: ClI
Reactant: Nc1ccnc(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(N2CCOCC2)ncc1I
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
To a stirred solution of 92.8 g (311 mmol, 60 wt % purity) 2-morpholin-4-yl-pyridin-4-ylamine in 1000 ml glacial acetic acid was added 76.5 g (932 mmol) sodium acetate and the mixture was then cooled to 15° C. in an ice-bath. A solution of 50.4 g (311 mmol) iodine monochloride in 200 ml glacial acetic acid was then added dropwise at a rate such that the reaction temperature remained at 10-15° C. After 40 min the addition was complete. The reaction mixture was then stirred for a further 20 min before being poured onto 1000 ml water. The mixture was concentrated in vacuo and the residue partitioned between THF/ethyl acetate (1:1) and saturated brine. 5 N aqueous sodium hydroxide solution was added until the aqueous phase was pH 14, whereupon some product precipitated. The crystals were collected by filtration to afford 16.9 g (18%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquid phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether and the resulting crystals collected by filtration to afford a further 47.2 g (50%) of 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquor was concentrated in vacuo and the residue was purified by flash chromatography (1/1-1/2 heptane/ethyl acetate) to afford a further 9.4 g (10%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. Meanwhile, the aqueous phase from the initial aqueous extraction was left to stand for 2 days whereupon crystals deposited. These crystals were collected by filtration to afford a further 5.2 g (5%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH2:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:8][C:7]1[C:2]([NH:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:6]=1[CH3:9]
Reactant: CCCN(CCC)C(=O)CN
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)nc(C)c1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A mixture of 4-chloro-5,6-dimethyl-2-phenylpyrimidine (1.0 g), 2-amino-N,N-dipropylacetamide (0.87 g) and triethylamine (0.55 g) is refluxed with stirring at 150° C. for three hours. To the reaction mixture are added water and chloroform, and the chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from a mixture of diethyl ether and n-hexane to give the desired compound (1.3 g), m.p. 79-80° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.[Cl:14]N1C(C)(C)C(=O)N(Cl)C1=O>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[C:3]=1[Cl:14]
Reactant: CCCc1nc(C=O)cc(N)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Product: CCCc1nc(C=O)c(Cl)c(N)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a flask equipped with a stir bar and reflux condenser was added 4-amino-5-fluoro-6-propylpicolinaldehyde (0.250 g, 1.372 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.149 g, 0.755 mmol). The flask was sealed, evacuated and backfilled with N2. Acetonitrile (13.72 mL) was added, and the reaction mixture was stirred at room temperature for ˜5 min, then heated to reflux (˜2 h). The reaction mixture color changed from yellow to orange then green over the course of 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with H2O. The layers were separated, and the organic layer was washed with dilute sodium bisulfite followed by saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated onto silica. Purification via flash chromatography (silica; EtOAc, Hex) yielded 4-amino-3-chloro-5-fluoro-6-propylpicolinaldehyde (97 mg, 32.6%) as an off-white solid: mp 89-91° C.; 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 4.81 (s, 2H), 2.81 (m, 2H), 1.76 (m, 2H), 0.99 (t, J=7.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −139.62; 13C NMR (101 MHz, CDCl3) δ 191.27, 152.80, 149.26, 146.64, 141.87, 139.82, 115.77, 37.04, 28.53.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][O:21][C:20]3=[O:25])[CH2:13][CH2:12]2)[N:2]=1.[CH3:26][NH2:27]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][C:23]([NH:27][CH3:26])=[O:24])[CH2:15][CH2:16]2)[N:2]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCC1CCN(c2cc3ccccc3cn2)CC1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2cc3ccccc3cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.24 g (0.71 mmol) of 3-{2-[1-(3-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 11.3, and 1.8 ml (3.53 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 96/4 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.16 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH:5]=[C:6]=[C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=[O:15])[CH:9]=[C:8]1[CH3:16].CN[C:20]1(NC)[CH:25]=CN=CC1.[OH2:28]>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[C:25]([O:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH:5]=[C:6]=[C:7]1[C:12]([CH3:13])([CH3:14])[CH2:11][C:10](=[O:15])[CH:9]=[C:8]1[CH3:16])(=[O:28])[CH3:20]
Reactant: CNC1(NC)C=CN=CC1
Reactant: O
Reactant: CC1=CC(=O)CC(C)(C)C1=C=C/C(C)=C/CO
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC/C=C(\C)C=C=C1C(C)=CC(=O)CC1(C)C
Yield: 48 %

Procedure:
To a solution of (3E)-4-(5-hydroxy-3-methyl-1,3-pentadien-1-ylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (1.2 g, 5.2 mmol) in acetic anhydride (5.0 mL) and triethylamine (5.0 mL) cooled to 0° C., was added 4,4-dimethylaminopyridine (25 n g). After 15 min. water was added to the reaction mixture, and the product was extracted three times with ether. The combined ethereal extracts were washed with sodium chloride solution, and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography over silica gel in the manner described in Example 1 above gave the desired product (680 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-])=O)=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:6]#[N:7].O>C(O)(=O)C.[Fe]>[NH2:21][C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1c(OCCCN2CCOCC2)ccc(C#N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(OCCCN2CCOCC2)ccc(C#N)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (7.7 g, 24.1 mmol) was suspended in acetic acid (170 mL) and cooled to 0° C. Water (0.4 mL) was added, followed by iron powder (6.7 g, 120 mmol) and the resulting mixture was stirred at room temperature for 4 h at which time the reaction mixture was filtered through a pad of Celite and washed with acetic acid (400 mL). The filtrate was concentrated under reduced pressure to 100 mL and diluted with EtOAc (200 mL) at which time potassium carbonate was added slowly. The resulting slurry was filtered through a pad of Celite washing with EtOAc and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and passed through a pad of silica gel. The resultant solution was concentrated under reduced pressure to provide the title compound (6.5 g, 92%): 1H NMR (DMSO-d6) δ: 7.13 (1H, d), 6.38 (1H, d), 5.63 (2H, br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H, br t), 2.41 (2H, t), 2.38 (4H, m), 1.88 (2H, quint.).