Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1OC
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1OC
Reaction time: 16 h

Procedure:
A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (3.73 g, 12.8 mmol) (prepared according to the process as disclosed in WO97/43287. Intermediate 7, page 24) and 2-chloro-5-(3,4-dimethoxyphenyl)pyrimidine (1.6 g, 6.4 mmol) in DMF (50 mL, anhydrous) was heated at 120° C. under stirring for 16 h. The reaction mixture was quenched with NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine (2×) and dried with MgSO4. Column chromatography (silica gel, ethyl acetate:hexanes=2:3) yielded a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[N:21]1>>[NH:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[N:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cc[nH]n1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc[nH]n4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-pyrazole-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-pyrazol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(CCc3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2c(CCc3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 60b (55.0 mg, 0.102 mmol) in DCM (2 mL) at RT was added TFA (500 μL, 6.53 mmol). After stirring at rt for 0.5 h, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:9 MeOH-DCM) to afford the title compound 79 (with 1.1 eq TFA) as a white solid. 1H-NMR (CDCl3; 400 MHz) δ: 8.03 (d, J=8.6 Hz, 2H), 8.00 (d, J=5.6 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.56-7.62 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.11 (d, J=5.6 Hz, 1H), 3.87-4.05 (m, 8H), 3.57 (t, J=7.1 Hz, 2H), 3.34-3.43 (m, 2H), 3.07-3.18 (m, 2H), 2.71-2.83 (m, 2H), 1.77-1.95 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C28H29N5O3, 484.2 (M+H). found 484.5.
Reaction SMILES: [NH2:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.[OH-].[K+].[ClH:29].[Cl-].[Na+]>CO.O>[ClH:29].[NH2:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1
Reactant: CCCCCC(N)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC(N)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of 1 g. of ethyl 15-amino-9-oxo-prostanoate (Example 143) in 15 ml. of methanol-water (1:1) containing 445 mg. of potassium hydroxide is stirred at ambient temperature for 18 hours. The solution is acidified with hydrochloric acid, saturated with sodium chloride, and extracted several times with methylene chloride. The organic phase is dried with anhydrous magnesium sulfate and taken to dryness to give a viscous oil; λ max. 2.80 - 3.70 (broad), 5.75, and 5.87 μ.
Reaction SMILES: [H-].[Na+].C(NC(C)C)(C)C.[CH:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.C([Li])CCC.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.Cl.ClCC1C=CN=CC=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCCC1.CCCCCC>[N:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:10]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:26][CH:27]=1
Reactant: O=C(O)C1CCCC1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)C1(Cc2ccncc2)CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.8 %

Procedure:
To a suspension of 3.69 g (123 mmol) of 80% sodium hydride in 150 mL of anhydrous tetrahydrofuran and 11.6 g (115 mmol) of diisopropylamine, at 0° C. was added 12.82 g (112 mmol) of cyclopentanecarboxylic acid. This was then heated at reflux for 15 minutes, cooled to 0° C. and 45 mL of 2.5M n-butyllithium in hexane added. After 15 minutes at 0° C. and 30 minutes at 35° C., the mixture was recooled to 0° C. and a solution of 14.4 g (112 mmol) of 4-chloromethylpyridine (freshly prepared from 4-chloromethylpyridine hydrochloride by neutralization with aqueous sodium bicarbonate, extraction with hexane, drying and concentrating) was added. After 30 minutes at 0° C. and 60 minutes at 35° C., the mixture was cooled to 0° C., water carefully added and extracted twice with diethyl ether. The aqueous layer was acidified to pH 3 with 6N hydrochloric acid whereupon a precipitate formed. The pH was adjusted to 5.9 with 10% sodium hydroxide and the solids collected. Recrystallization from hot ethanol and hexane afforded 5.7 g of desired product, m/e 206 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[N:6][C:7]=1[O:8][C@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:15][C:4]2[CH:5]=[N:6][C:7]([O:8][C@H:9]([CH3:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: C[C@@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a mixture of 5-chloro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 235, 360 mg, 0.86 mmol) and 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 12, 242 mg, 0.86 mmol) in DMSO (2 mL) was added K2CO3 (237 mg, 1.7 mmol) at room temperature under N2 and the resulting mixture was stirred for 5 hours. The reaction was quenched with water and extracted with DCM (3×5 mL). The mixture was filtered through a phase separation cartridge. The combined organic phases were washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product. The crude product was purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to give the title compound (429 mg, 99%) as colourless gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C.[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[OH:13][CH:14]([CH2:23][OH:24])[CH2:15][N+]1C=CC=CC=1C.[OH:25][CH:26]([CH2:35][OH:36])[CH2:27][N+]1C=CC=CC=1C.N1C=CC(C)=CC=1.S([O-])([O-])(=O)=O.OC(CO)C[N+]1C=CC(C)=CC=1.OC(CO)C[N+]1C=CC(C)=CC=1>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[OH:13][CH:14]([CH2:23][OH:24])[CH2:15][N+:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:25][CH:26]([CH2:35][OH:36])[CH2:27][N+:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc[n+]1CC(O)CO
Reactant: Cc1ccccn1
Agent: Cc1cc[n+](CC(O)CO)cc1
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccncc1
Product: OCC(O)C[n+]1ccccc1

Procedure:
In analogy to the above-described procedure, α-picoline was used as a starting material to prepare bis-N-(2,3-dihydroxypropyl)-α-picolinium sulfate, which has the formula ##STR5## This compound was found to have a refractive index of nD20 =1.5268. Similarly, γ-picoline was used as a starting material to prepare bis-N-(2,3-dihydroxypropyl)-γ-picolinium sulfate, which has the formula ##STR6## and which had a refractive index of nD20 =1.5272.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH:4][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9]
Reactant: CCC(C)CN
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCC(C)CNCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of (+/−)-2-methylbutylamine (10 g, 115 mmol) in tetrahydrofuran (80 mL) was slowly added a solution of 1,3-propane sultone (13.5 g, 109 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×30 mL). The solid was suspended 95% Acetone/EtOH (200 mL). The suspension was stirred at room temperature for 5 minutes. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound DS (17.6 g, 78%). 1H NMR (D2O, 500 MHz) δ ppm 3.07 (t, 2H, J=7.8 Hz), 2.93 (m, 3H), 2.76 (m, 1H), 2.01 (m, 2H), 1.67 (m, 1H), 1.30 (m, 1H), 1.09 (m, 1H), 0.81 (d, 3H, J=6.8 Hz), 0.77 (t, 3H, J=6.8 Hz). 13C NMR (D2O, 125 MHz) δ ppm 53.48, 48.13, 46.92, 31.96, 26.38, 21.29, 16.11, 10.19. ES-MS 210 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C@@H:4]1[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:15])([CH3:1])[C@H:3]1[OH:14])[C:21](=[O:26])[C:20]2=[O:27]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2C(=O)C(=O)c3cc(Cl)ccc32)[C@@H]1O

Procedure:
Following the procedure described in the Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-1H-indole-2,3-dione as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O[CH:22]=[C:23]1[C:34]2[C:26](=[CH:27][CH:28]=[C:29]3[C:33]=2[S:32][CH:31]=[N:30]3)[NH:25][C:24]1=[O:35])C>>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:11]([CH3:12])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:22]=[C:23]2[C:34]3[C:26](=[CH:27][CH:28]=[C:29]4[C:33]=3[S:32][CH:31]=[N:30]4)[NH:25][C:24]2=[O:35])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CN(CCOCCO)S(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H), 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI-MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI-MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI-MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H, 4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [C:1]([C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])([O:3][CH3:4])=[O:2]>C(O)(=O)C.[Pd]>[C:1]([CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C(=Cc1cccc(OC)c1)CC(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C(CC(=O)O)Cc1cccc(OC)c1
Yield: 83.1 %

Procedure:
A solution of 21.1 g (84 mmol) of 3-carbomethoxy-4-(3-methoxyphenyl)-3-butenoic acid in 100 ml of acetic acid with 2.11 g of 10% Pd on carbon is shaken under H2 atmosphere until H2 uptake ceases (approximately 4 hours). This is filtered through celite and the filtrate concentrated in vacuo several times from toluene to afford 17.6 g of 3-carbomethoxy-4-(3-methoxyphenyl)butanoic acid in the form of a yellow oil which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:14]([O:16]C)=[O:15].[OH-].[Na+:24]>CO>[F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:14]([O-:16])=[O:15].[Na+:24]
Reactant: COC(=O)c1cc2ccncc2n1Cc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cc2ccncc2n1Cc1ccc(I)cc1F
Yield: 109.7 %

Procedure:
To a solution of methyl 1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.46 g, 1.09 mmol) in methanol (4 ml) was added 1M aqueous solution of sodium hydroxide (1.4 ml, 1.40 mmol) and the reaction was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (15 ml), methanol (15 ml), toluene (15 ml) and dichloromethane to afford the crude title compound as a waxy white solid (0.50 g, quantitative yield). LCMS (method B): RT=2.11 min, (M−H)−=395; M+H+=397.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:8]2[CH3:11])=[C:4](I)[CH:3]=1.[Cu][C:28]#[N:29].ClCCl.C(O)C>CN(C)C=O>[C:28]([C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:25])[N:7]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH:8]2[CH3:11])#[N:29]
Reactant: N#C[Cu]
Reactant: CC1c2cc(F)cc(I)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CC1c2cc(F)cc(C#N)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.2 %

Procedure:
Tert-butyl 4-(6-fluoro-4-iodo-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-1-carboxylate (240 mg, 0.5 mmol) and copper(I) cyanide (67 mg, 0.75 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the resulting solution was refluxed under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (174 mg, 93% yield).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17].[SH2:19].[Na]>C(O)C>[CH3:7][N:6]1[C:2]([SH:19])=[C:3]([C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:4]([CH3:8])=[N:5]1
Reactant: S
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nn(C)c(S)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 33.3 %

Procedure:
A mixture of 0.3 g. of 5-chloro-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole, 2.1 g. of sodium hydrogen sulfide 2 hydrate and 6 ml. of ethanol is heated under reflux on a water bath for 3 hours. After completion of the reaction, the ethanol is distilled off under reduced pressure from the reaction mixture and 15 ml. of water is added followed by extraction with benzene. To an aqueous layer is added conc. hydrochloric acid to adjust the pH to 1 and the mixture is extracted with chloroform. The extract is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off from the extract to give the crude crystalline substance, which is then recrystallized from n-hexane to give 0.10 g. of the desired product as yellow powders having a melting point of 85°-86° C. Yield 33.3%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(C(=O)O)C(C)C)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 1.2 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoate (0.109 g; 0.267 mmol) in methanol (2.7 mL) was added a solution of sodium hydroxide 5 N (0.53 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. A purification by preparative TLC using a mixture ethyl acetate/heptane (1:1)+0.5% AcOH furnished 0.0013 g (12%) of the title compound as a light yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[C@@H:24]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[ClH:26].[C@H:15]1([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[C@@H:24]2[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The ester 62 (3.8 g, 10.8 mmol) is dissolved in 15 ml of dioxane and after addition of 70 ml of a 4M solution of HCl in dn of HCl in dioxan the mixture is stirred for 4 hours at RT. The product is filtered off and is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][N:7]=1.[Cl:14]C1C(Cl)=CC=CN=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[C:11]([Cl:14])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)CSc1ccc(Cl)cn1
Reactant: Clc1cccnc1Cl
Product: COC(=O)CSc1ncccc1Cl

Procedure:
(3-Chloro-pyridin-2-ylsulfanyl)-acetic acid methyl ester (18) was synthesized according to the procedure used for compound 14. Starting with 2,3-dichloropyridine (17, 2.09 g, 14.0 mmol) the target 18 was obtained as a colorless oil (1.6 g, 52% yield).
Reaction SMILES: [Se:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][Se:1](=[O:10])[C:5]=2[CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=[Se]1C=Nc2ccccc21
Solvent: O
Product: O=C(c1ccccc1)c1ccc2c(c1)[Se](=O)C=N2
Temperature: 130 °C

Procedure:
1.98 g (0.01 mol) of benzoselenazolinone, 50 to 60 g of polyphosphoric acid and 1.35 g (0.011 mol) of benzoic acid are introduced into a 100-cm3 round-bottomed flask. The mixture is heated on an oil bath to a temperature of 130° C. for a time T of 3 hours, with stirring. The reaction mixture is then hydrolyzed in 300 cm3 of cold water. The product is drained, washed with water, dried and recrystallized.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(m-tolyl)-oxazole-4-carboxylic acid.