Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CC(C)=O>[CH3:1][C:2]1[N:6]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH2:22][CH3:23])=[O:10])[N:5]=[N:4][N:3]=1
Reactant: CCI
Reactant: Cc1nnnn1-c1ncccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccnc1-n1nnnc1C

Procedure:
2-(5-Methyl-1H-tetrazol-1-yl)nicotinic acid (5.6 g, 27 mmole) was suspended in acetone (250 mL), potassium carbonate (5 g) and ethyl iodide (5 mL) were added and the reaction mixture was heated at reflux for 2 hours. The acetone was removed under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, dried, then concentrated under vacuum to provide 6.3 g of ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[CH:21](OC)=[O:22]>C1COCC1.Cl>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:21]=[O:22]
Reactant: COC=O
Reactant: Clc1cncc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexanes, 9.3 ml, 14.9 mmol) was added dropwise at 0° C. to a solution of diisopropylamine (1.95 ml, 14.9 mmol) in THF (30 ml). After 15 min. at 0° C., the solution was cooled to −78° C. and 3,5-dichloropyridine (2.0 g, 13.5 mmol) was added. After 1 h, methyl formate (0.92 ml) was added and the mixture warmed to room temperature over 2 h, diluted with 1N hydrochloric acid and extracted twice with ethyl acetate. The extracts were washed with brine, dried over sodium sulphate and evaporated to give a yellow oil which solidified, m.p. 110-111° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([N:26]([CH3:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1.C(Cl)Cl>[ClH:34].[CH3:33][N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[N:22]=[C:23]([NH2:25])[N:24]=[C:19]([C:16]2[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:18][N:17]=2)[N:20]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl-4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Intermediate 106, 934 mg, 2.06 mmol) and 4M hydrogen chloride in 1,4-dioxane (5 mL) was combined in DCM (5 mL) at 0 C. The reaction was warmed to RT and left to stir for 18 h. The mixture was concentrated under reduced pressure to give title compound as a yellow solid (832 mg). Method B HPLC-MS: MH+ requires m/z=352 Found: m/z=353, Rt=1.23 min (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15](N)[N:16]=[C:4]2[N:3]=1.N([O-])=O.[Na+].C(OCC)(=O)C.C(Cl)[Cl:29]>Cl.O.C(Cl)Cl.C(OCC)(=O)C>[Cl:29][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]2[N:14]=1
Reactant: ClCCl
Reactant: Cc1cc(-c2ccccc2)n2nc(N)nc2n1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2ccccc2)n2nc(Cl)nc2n1
Reaction time: 0.17 h

Procedure:
To 2.0 g (8.9 mmol) of 5-methyl-7-phenyl-1,2,4triazolo[1,5-a]pyrimidin-2-amine stirring in 25 ml of concentrated hydrochloric acid, 1.2 g (17.4 mmol) of sodium nitrite dissolved in 4.0 ml of water was added dropwise at ambient temperature. After the addition, the reaction suspension was warmed at about 60° for 15 minutes followed by stirring another 10 minutes without heat. Ethyl acetate (150 ml) and excess water were added. The ethyl acetate layer was separated whereby a certain amount of insoluble material present was ignored and the extract washed with water (2X), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid residue. Silica gel column chromatography (methylene chloride followed by 10:1 methylene chloride/ethyl acetate) afforded the title compound, m.p. 179°-181° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5]2.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])(=O)C.[K+].BrC1C=CC2C(=CC=CC=2)N=1>C(O)C.O>[C:19]1([CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5]2
Reactant: COC(=O)C=Cc1cnc2ccc(Br)cc2c1
Reactant: Cc1ccccc1B(O)O
Agent: Brc1ccc2ccccc2n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)C=Cc1cnc2ccc(-c3ccccc3C)cc2c1

Procedure:
5-Bromo-2-nitrobenzaldehyde 1 (6.03 g, 26.2 mmol) was dissolved in MeOH (200 mL) and treated with 5N HCl (10 mL). The mixture was heated to 70° C. and iron powder (7.32 g, 131 mmol) was added in five portions every 5 min. Upon completion (by TLC) the reaction was cooled and DCM (200 mL) was added before filtering through a pad of celite. The filtrate was concentrated under reduced pressure to 150 mL. To this material, a solution of 1,1,3,3-tetramethoxypropane (9.52 ml, 57.7 mmol) in 5N HCl (10 mL) pre-mixed for 45 min was added. The reaction mixture was stirred at 80° C. for 60 min. Toluene (100 mL) and acetic acid (40 mL) were added and the solution was heated to 110° C. for 3 h, then cooled and evaporated to dryness under reduced pressure. The crude material was purified using silica chromatography (20-60% ethyl acetate in hexane gradient) to give 6-bromoquinoline-3-carbaldehyde 2. Step 2 6-Bromoquinoline-3-carbaldehyde 2 (2.8 g, 12.0 mmol) and methyl(triphenylphosphoranylidene)acetate (4.0 g, 12.0 mmol) were dissolved in dry THF (50 mL) and heated to 50° C. After 40 min the solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 60% ethyl acetate in hexane gradient) gave methyl 3-(6-bromoquinolin-3-yl)acrylate 3 as a mixture of E and Z isomers. Step 3 Methyl 3-(6-bromoquinolin-3-yl)acrylate 3 (0.91 g, 3.1 mmol), 2-methylphenyl boronic acid (R1 substituted ring A in 4 above; 0.61 g), potassium acetate (1.0 g) and bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)dichloropalladium (II) (0.19 g) were suspended in ethanol (70 mL) and water (5 mL) and heated to reflux for 90 min. LC/MS showed the bromoquinoline had been consumed the reaction was evaporated to dryness under reduced pressure. The crude was partitioned between ethyl acetate and water. The organic layer was separated and dried with magnesium sulfate, evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to ethyl acetate gradient) to give methyl 3-(6-o-tolylquinolin-3-yl)acrylate 4 (representative compound 4 wherein ring A is ortho-toluene).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:7]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCCCc1ccc(O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C
Yield: 70.8 %

Procedure:
A mixture of 4-butyl-3-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenol (0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 5-15% ethyl acetate/hexanes to give a yellow oil (0.12 g, 68%). 1H NMR (400 MHz, CDCl3) δ8.04 (dd, J=6.9, 1.7 Hz, 2H), 7.65 (q, J=7.8 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.1, 2.2 Hz, 1H), 4.25-4.18 (m, 4H), 2.98 (t, J=6.4 Hz, 2H), 2.48 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.57 (s, 6H), 1.44 (penta, J=7.6 Hz, 2H), 1.33-1.24 (m, 5H), 0.86 (t, J=7.1 Hz, 3H), MS (ES) m/e 542 (M+1).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[OH:14][CH2:15][C:16]#[C:17][C:18]1[N:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]([C:29](OCC)=[O:30])[C:21]2=[O:34]>C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:29]([C:22]2[C:21](=[O:34])[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:17]#[C:16][CH2:15][OH:14])[N:19]=3)[N:24]([CH3:28])[CH:23]=2)=[O:30])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cn(C)c2ccc(C#CCO)nc2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2nc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
Trimethylaluminum (2M in toluene, 42 μL) is added dropwise to a room temperature solution of 4-chlorobenzylamine (17 μL) in CH2Cl2 (1 mL) under nitrogen. The solution is stirred for 5 minutes before the addition in one portion of ethyl 6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxylate (Preparation 60, 20 mg). The resulting suspension is stirred at room temperature for 3.5 h. The reaction mixture is partitioned with dil. aq. HCl (2 mL) and extracted with CH2Cl2 (2×2 mL). After drying over MgSO4, the extracts are concentrated under vacuum. The crude residue is purified by flash chromatography (9 g silica, 10% methanol/CH2Cl2) to give 14 mg (52%) of the title compound as a It. yellow solid. Physical Characteristics: Rf (15% methanol/CH2Cl2)=0.53; 1H NMR (DMSO-d6) δ10.32, 8.90, 8.31, 7.90, 7.40, 7.36, 5.5, 4.58, 4.39, 4.01; HRMS (FAB) m/z 382.0963 (C20H16ClN3O3+H). Anal. Found (C20H16ClN3O3.0.24 H2O): C, 62.21; H, 4.21; N, 10.75.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.FC1C=CC(C2N(C(C)C)N=C3C=2CC(C)NCC3)=CC=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:12]2[N:13]([CH:19]([CH3:20])[CH3:21])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH:17]([CH3:18])[CH2:16]3)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Agent: CC1Cc2c(nn(C(C)C)c2-c2ccc(F)cc2)CCN1
Product: CC1Cc2nn(C(C)C)c(-c3ccc(F)cc3)c2CCN1

Procedure:
The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 115 of 4-fluorophenylboronic acid. The reaction sequence also yielded 3-(4-fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C17H22FN3, 287.18. found, m/z 288.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.32-7.28 (m, 2H), 4.36 (m, 1H), 3.61-3.56 (m, 1H), 3.50-3.47 (m, 1H), 3.20-3.08 (m, 3H), 2.85-2.80 (m, 1H), 2.73-2.69 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.41-1.38 (m, 6H).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (5 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 4-methoxybenzoyl chloride (17) (587 mg, 3.44 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 17 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 50 g, dichloromethane/ethyl acetate=9/1). The residue was further recrystallized from ethyl acetate to give Compound 11x (592 mg, 1.39 mmol, 80.8%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 3.85 (s, 3H), 4.17 (s, 2H), 7.04-7.11 (m, 4H), 7.14-7.26 (m, 5H), 7.93-7.98 (AA′BB′, 2H), 8.05-8.11 (AA′BB′, 2H), 8.96 (s, 1H), 10.63 (s, 1H); 13C NMR (67.8 MHz, DMSO+CDCl3) 40.3, 54.7, 54.8, 112.9 (2C), 113.7 (2C), 125.4, 125.7, 127.4 (2C), 127.7 (2C), 128.0, 128.5 (2C), 129.4 (2C), 136.2, 137.6, 143.6, 148.2, 150.4, 160.1, 162.0, 165.5; IR (KBr, cm−1) 700, 743, 843, 1030, 1159, 1177, 1258, 1290, 1452, 1485, 1514, 1535, 1580, 1609, 1643, 3242; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.48; H, 5.40; N, 9.94.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10][C:11](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:12]>>[C:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:10]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 100 g of isonipecotic acid and 40 ml of acetic anyhydride isrefluxed for 2 hours and then allowed to stir at room temperature overnight. The reaction mixture is then evaporated under reduced pressure and the residue triturated with diethyl ether. The resulting solids are recrystallized from a mixture of isopropanol and diethyl ether to afford the N-acetyl isonipecotic acid, melting at 175°.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][OH:38]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: CN(C)CCO
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCCN(C)C)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 2-(dimethylamino)ethanol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[N:4]=[CH:3]1.[CH3:14][NH:15][CH3:16].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:14][N:15]([CH3:16])[C:11]([C:10]1[C:5]2[N:4]=[CH:3][NH:2][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C(O)c1cccc2[nH]cnc12
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid hydrochloride (1 g, 5.04 mmol), dimethylamine (2M in THF; 3.78 mL, 7.55 mmol) and ethyldiisopropylamine (3.51 mL, 20.1 mmol) in DMF (5.0 mL) at room temperature was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (1.95 g, 5.14 mmol) in a single portion. The mixture was stirred at room temperature overnight then concentrated in vacuo. The product was purified by SiO2 chromatography followed by trituration with Et2O providing 1H-benzoimidazole-4-carboxylic acid dimethylamide (730 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reaction time: 8 h

Procedure:
770 mg (3.83 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 467 mg (3.83 mmol) of 4-hydroxybenzaldehyde were dissolved in 20 ml of THF. 1.2 g (4.6 mmol) of triphenylphosphine and 790 mg (4.6 mmol) of N,N,N′,N′-tetramethylazodicarboxyamide were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:17])[CH:8]=[CH:9][CH:10]=1
Reactant: Fc1ccccc1Oc1cccnc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: [O-][n+]1cccc(Oc2ccccc2F)c1
Reaction time: 16 h

Procedure:
A solution of 30 g of 3-(o-fluorophenoxy)pyridine in 50 ml of glacial acetic acid is treated at 35° C. with 33 g of 40% peracetic acid in acetic acid in four portions. The mixture is stirred for 16 hours, refluxed 1 hour and 50 ml of isopropanol is added and the heating continued at 95° C. for 1 hour. The mixture is concentrated at reduced pressure and is dissolved in 300 ml of dichloromethane. The solution is washed with excess 25% sodium hydroxide solution. The dichloromethane solution is dryed over anhydrous MgSO4, filtered and concentrated at reduced pressure. The 3-(o-fluorophenoxy)-pyridine N-oxide crystallizes, mp 89°-95° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:11]1([N:10]=[C:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C(=Nc1ccccc1)=Nc1ccccc1

Procedure:
1,3-Diphenylthiourea (22.8 g), triphenylphosphine (10.1 g) triethylamine (10.1 g) and carbon tetrachloride (21.6 g) were refluxed for 4 hours in methylene chloride (300 ml). The solvent was removed under vacuum. The residue was shaken with hexane (300 ml); the hexane solution was evaporated and the residue was distilled to afford the title compound as an oil bp 115°-120°/0.3 mm. Similarly, by using this procedure, but employing other 1,3-disubstituted thioureas instead of 1,3-diphenylthiourea, other carbodiimides can be made.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH:11]=[CH:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(C=CCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(COc3ccc(C=CCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
13 mg (0.50 mmol) 95% sodium hydride were given to a solution of 108 mg (0.50 mmol) 4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was collected, washed with water (2×10 ml), methanol (2×10 ml), diethyl ether and dried in vacuum at 40° C. to yield 225 mg (86%) of product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[C:24]([OH:30])(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:28][CH2:27][CH2:26][CH2:25][C:24]([OH:30])=[O:29])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:23])[NH:19][S:20]1(=[O:21])=[O:22]
Reactant: C=CCCC(=O)O
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: O=C(O)CCCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and pent-4-enoic acid analogous to Example 44: (M−1)−=327.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:15]1[C:14]([C@H:11]2[C@H:10]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=[C:17]([F:20])[CH:16]=1
Reactant: Fc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2COc2ccc3c(c2)OCO3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Yield: 98.7 %

Procedure:
A solution containing 8.4 g (0.02 mol) of (−)trans-1-benzyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine in 120 ml of ethanol is hydrogenated in an autoclave in the presence of 0.6 g of 10% palladium-on-carbon catalyst at 30 to 40° C. under 2×105 Pa pressure for 2 to 3 hours. After taking up the hydrogen, the catalyst is filtered under nitrogen gas and the filtrate is evaporated to solvent-free to give 6.5 g of paroxetine base as evaporation residue in the form of a colourless oil. The product is suspended in 80 ml of water and after adding 2 ml of glacial acetic acid, it is stirred until dissolution. Then, the solution of 2 g of ammonium chloride in 10 ml of water is added to the mixture. After stirring for 4 hours, the precipitated crystalline title product is filtered at 10° C., twice washed with 10 ml of cold water each and dried on air to obtain 6,5 g (89%) of title compound, m.p.: 136-138° C.; [α]D20−86.6° (c=1, methanol).