Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=1.CN(C)[CH:23]=[O:24]>>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:23]=[O:24])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=1
Reactant: CN(C)C=O
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Phosphorus oxychloride (3.36 ml) is added dropwise over a period of 20 minutes to dimethylformamide (10.6 g) maintained at 0°-3°. After complete addition a solution of 2-(3-pyridyl)indole (6.50 g) in dimethylformamide (20 ml) is added dropwise over a period of 30 minutes at such a rate so that the reaction temperature does not exceed 10°. The cooling bath is then removed and the viscous solution heated to and maintained at 35°-40° for 1 hour. The reaction mixture is treated with crushed ice (50 g). A solution of sodium hydroxide (24.4 g) in 65 ml of water is added slowly. After the addition the resulting red-orange solution is heated rapidly to reflux and maintained at reflux for about 2 minutes. The solution is allowed to cool to room temperature, then placed in a freezer for 2 days. The resulting precipitate is collected and washed well with water to give an orange solid which is recrystallized from methanol (240 ml) to give 2-(3pyridyl)-indole-3-carboxaldehyde, m.p. 236°-238°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([NH:18][C:19]3[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: COC(=O)c1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(NC(=O)c2cn(Cc3ccc(Cl)c(Cl)c3)nn2)s1
Temperature: 40 °C
Reaction time: 72 h
Yield: 43.4 %

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (1 g, 3.6 mmol), methyl 2-amino-1,3-thiazole-5-carboxylate (0.58 g, 3.6 mmol), HATU (1.82 g, 1.3 eq) and DIPEA (0.9 mL, 1.3 eq) in DMF (50 mL) was stirred at 40° C. for 3 days. The solvent was evaporated and the residue was washed with water and extracted with DCM. A precipitate was formed, filtered and triturated with a mixture of methanol/acetonitrile. After filtration, the yellow solid was dried to give the title compound as a pale yellow solid (644 mg, 44%). LC/MS: m/z 412 (M+H)+. Rt: 3.21 min.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:10])C.C(O)(=O)C.Cl>C(O)C>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]12[CH2:18][CH:17]3[CH2:19][CH:13]([CH2:14][CH:15]([CH2:16]3)[CH2:20]1)[CH2:12]2)=[O:10]
Reactant: CCOC(CCCNC(=O)C12CC3CC(CC(C3)C1)C2)OCC
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=CCCCNC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h

Procedure:
1.94 g (6 mmol) N-(4,4-diethoxybutyl)adamantylcarboxamide, 7.5 mL of acetic acid, 3.75 mL of 1N aqueous hydrochloric acid and 30 mL ethanol are put together and stirred for 16 hours under argon atmosphere. Ethanol is evaporated. Then the resulting residue is dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase is dried with sodium sulfate and the solvent evaporated in vacuum.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:27]([NH:30][CH3:31])(=[O:29])=[O:28].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[O:9])=[C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:5]=[CH:4][C:3]=1[S:27]([NH:30][CH3:31])(=[O:29])=[O:28]
Reactant: CNS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1F
Reactant: C1COCCN1
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1F

Procedure:
The title compound was prepared according to the procedure described for example 202 from 2,4-Difluoro-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide (example CD) and morpholine to yield the title compound as a colourless foam, MS (m/e): 529.3 (M+H, 100%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][C:1]1[O:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1
Reactant: CCOC(=O)C(=O)NNC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnc(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of ethyl 2-(2-acetylhydrazinyl)-2-oxoacetate (0.50 g, 2.87 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.53 mL, 3.73 mmol) and p-TsCl (0.65 g, 3.44 mmol) in three portions. The reaction mixture was stirred at rt for 8 h then was diluted with CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by column chromatography using EtOAc/hexanes to give the title compound as an off-white solid (375 mg, 84%). 1H NMR (300 MHz, CDCl3): δ 4.51 (2H, q, J=7 Hz), 2.65 (3H, s), 1.52 (3H, t, J=5 Hz). MS (M+H): 157.1.
Reaction SMILES: [Na].[CH3:2][SH:3].Cl[CH2:5][CH2:6][CH2:7][N:8]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:22][CH3:23])[CH2:13]1)[CH2:9][CH2:10][CH3:11]>C(O)C>[CH3:23][O:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][CH:12]([N:8]([CH2:7][CH2:6][CH2:5][S:3][CH3:2])[CH2:9][CH2:10][CH3:11])[CH2:13]2
Reactant: CS
Reactant: CCCN(CCCCl)C1CCc2c(cccc2OC)C1
Agent: [Na]
Solvent: CCO
Product: CCCN(CCCSC)C1CCc2c(cccc2OC)C1
Reaction time: 1 h

Procedure:
2.35 g sodium are dissolved in 50 ml absolute ethanol and immediately 4.8 g methylmercaptan in 60 ml ethanol are added dropwise. The mixture is warmed to 45° and at this temperature a solution of 19.7 g 2-[N-(3-chloropropyl)-N-propylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene in 120 ml absolute ethanol are added. The mixture is stirred at 50° for 1 hour. The residue is partitioned between ether and water. The ether phase is dried over potassium carbonate, filtered and concentrated. The resultant oil containing the heading compound is used further as such.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[N:21]=[CH:20]2)[NH:12][N:11]=1)([CH3:9])[CH3:8].[CH2:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1F)[C:35]#[N:36])[CH3:31].O>CS(C)=O>[CH2:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:12]1[C:13]2[C:18](=[C:17]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[N:21]=[CH:20]3)[CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]([CH3:9])[CH3:8])=[N:11]1)[C:35]#[N:36])[CH3:31]
Reactant: CCc1cc(C#N)ccc1F
Reactant: CC(C)c1n[nH]c2cccc(-n3cnc(-c4cnn(C)c4)c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)cccc21
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
Cesium carbonate (850 mg) was added to a solution of compound (5a) (200 mg) in DMSO (2.2 mL), and the mixture was heated to 130° C. The mixture was stirred for 10 minutes and 3-ethyl-4-fluorobenzonitrile (292 mg) was added thereto. The resulting mixture was stirred at the same temperature for 1.5 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling, and water was poured thereto. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate/methanol) to obtain compound (6a) (151.8 mg, yield 54%) as a white foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:26])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Yield: 31 %

Procedure:
To a solution of Example 26 (15 mg, 0.05 mmol) in MeOH (10 mL) was added thionyl chloride (1 mL) at rt. The reaction was stirred at reflux for 2 days. The solution was concentrated and purified by prep-HPLC to give 5 mg (31%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 0.70-0.73 (2H, m), 1.0-1.04 (2H, m), 2.0-2.04 (1H, m), 3.96 (2H, s), 4.74 (3H, s), 7.08 (1H, d, J=1.6 Hz), 7.14 (1H, dd, J=2.0, 8.4 Hz), 7.25 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=4.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.13 (1H, s). [M+H] Calc'd for C17H17ClN2O2, 317; found, 317.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:12]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise 4-(hexyloxy)benzoyl chloride (890 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1073 mg) was obtained as a white solid (91%) in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[O:1][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2C(=O)OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 35.3 g of methyl 3-hydroxybenzoate and 50.0 g of methyl 2-chloro-5-nitrobenzoate, dissolved in 400 ml of N,N-dimethylformamide, was added 48.1 g of anhydrous potassium carbonate. The mixture was stirred for 3 hours at 80° C. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by recrystallization from methanol to yield 75.4 g of methyl 2-(3-methoxycarbonylphenoxy)-5-nitrobenzoate (melting point: 97-99° C.) (Reaction Scheme (27) described below).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Na].Br[C:7]1[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([NH2:16])[C:8]=1[C:9]#[N:10]>O>[NH2:16][C:11]1[C:8]([C:9]#[N:10])=[C:7]([O:3][CH2:2][CH2:1][OH:4])[N:14]=[C:13]([NH2:15])[CH:12]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: OCCO
Agent: [Na]
Solvent: O
Product: N#Cc1c(N)cc(N)nc1OCCO
Temperature: 150 °C
Yield: 44 %

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 3 mL of ethylene glycol and 50 mg (2.2 mmol) of sodium. The mixture was stirred at 95° C. until all of the sodium had reacted, then 213 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled. The mixture was diluted with 15 mL of water, and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate layers were back extracted with water (1×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to provide 85 mg (44%) of a solid. 1H NMR (300 MHz, d6-DMSO) δ 6.20 (s, 2H), 6.16 (s, 2H), 5.32 (s, 1H), 4.76 (t, 1H, J=5.3 Hz), 4.21 (m, 2H), 3.64 (q, 2H, J=5.4 Hz); MS (ESI) m/e=151 (M−EtOH+H)+, 195 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: OCc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc(CO)nc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89 mg, 0.2 mmol) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid (61.2 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was diluted in MeOH, treated with Si-Thiol (100 mg), the resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH) afforded the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=475.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.77-1.86 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.11-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.12-4.22 (m, 1H) 4.61 (d, J=5.87 Hz, 2H) 4.84 (d, J=3.13 Hz, 1H) 5.47 (t, J=5.87 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.53 (d, J=8.21 Hz, 1H) 7.74-7.88 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[NH2:19])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#N.O.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(O)(=O)C>[CH3:18][C:14]1[C:13]2[NH:19][C:6](=[O:24])[C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:21])([F:20])[F:1])[C:4]=3[S:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(Sc2c(C#N)cccc2C(F)(F)F)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1NC(=O)c1cccc(C(F)(F)F)c1S2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Trifluoromethyl-2-(3-methyl-2-aminophenylthio) benzonitrile (2.53 g, 8 mmol) was dissolved in acetic acid (25 ml), water (25 ml) and concentrated sulphuric acid (25 ml) and the mixture stirred and heated under reflux for 7.5 hours, then at ambient temperature for 15 hours before further sulphuric acid (25 ml) was added and the mixture stirred and heated under reflux for a further 8.5 hours. The mixture was allowed to stand at ambient temperature overnight then poured onto crushed ice (200 ml) and basified to pH 4 with aqueous sodium hydroxide (10N). The mixture was extracted with dichloromethane (3×200 ml) and the combined organic fractions dried (magnesium sulphate) and evaporated. The residue was dissolved in xylene (400 ml) and heated under reflux for 72 hours in a Dean-Stark apparatus, before being allowed to cool. After evaporation of the xylene, recrystallisation from toluene, followed by recrystallisation from ethanol, the title compound was obtained as an off-white solid (1.02 g, m.p. 273°-277°).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][C:9]=2[F:17])=[C:5]([OH:20])[CH:4]=1)[CH3:2].Cl.[CH3:22][O:23][NH2:24].C(N(CC)CC)C>C(O)C>[CH3:22][O:23]/[N:24]=[C:14](/[C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[OH:20])=[C:9]([F:17])[CH:10]=1)\[CH3:15]
Reactant: CON
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(O)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc(/C(C)=N/OC)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone (46 mg; 0.17 mmol), under argon, in ethanol (1 mL), was added O-methylhydroxylamine hydrochloride (14 mg; 0.17 mmol) and 0.05 mL of triethylamine. The reaction was stirred to room temperature overnight. The mixture was concentrated in vacuo to give the desired product as light brown oil after purification by preparative TLC (14.5 mg; 0.048 mmol; 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[N:16]1.[F:22][C:23]([F:28])([F:27])[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:25][CH2:24][C:23]([F:28])([F:27])[F:22])=[N:16]1
Reactant: OCCC(F)(F)F
Reactant: Cc1cc(F)c(-n2nc(O)cc2C)cc1SCC(F)(F)F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2nc(OCCC(F)(F)F)cc2C)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
0.6 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxy-5-methylpyrazole was dissolved in 4 mL of tetrahydrofuran, and 0.23 g of 3,3,3-trifluoropropanol, 0.75 g of triphenylphosphine and 0.71 g of 1,1′-(azodicarbonyl)dipiperidine were added, followed by stirring at room temperature for 12hours. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:4) to obtain 0.61 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methyl-3-(3,3,3-trifluoropropoxy)pyrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:10][N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cn1cc(Br)cc(N(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(N(C(=O)OC(C)(C)C)c3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.0 g, 2.45 mmol) in DCM (49 ml) was added 1-methylpiperazine (491 mg, 4.9 mmol), sodium triacetoxyborohydride (1.3 g, 6.12 mmol) and acetic acid (294 mg, 4.9 mmol). The reaction mixture was heated to 40 degrees centigrade and stirred overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 20% methanol in DCM to give 1.08 g (89.5%) of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[C:6]=1[F:13])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([F:13])[C:7]=1[F:12]
Reactant: [N-]=[N+]=NCc1ccc(Br)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Br)c(F)c1F
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (164 mg, 0.60 mmol) in THF (3 mL) were added polymer-supported Ph3P (2.0 eq.) and water (1 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.42 min; [M+CH3CN+H]+=263.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([CH:20]2[S:25][CH2:24][CH2:23][CH2:22][S:21]2)=[N:18][N:19]=1>C1(C)C=CC=CC=1>[S:21]1[CH2:22][CH2:23][CH2:24][S:25][CH:20]1[C:17]1[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:19][N:18]=1
Reactant: Nc1nnc(C2SCCCS2)s1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C2SCCCS2)s1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 1.0 g. of 2,6-dimethoxybenzoyl chloride and 1.1 g of 2-amino-5-(1,3-dithian-2-yl)-1,3,4-thiadiazole in 20 ml of toluene was heated at reflux for eighteen hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a white solid. The solid was chromatographed over silica gel to provide 1.2 g (60% yield) of N-[5-(1,3-dithian-2-yl)-1,3,4-thiadiazol-2-yl)-2,6-dimethoxybenzamide.
Reaction SMILES: [CH:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>CCOCC>[CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C/C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCC/C=C/CO

Procedure:
Trans-2-nonenal (7.0 g, 0.05 mole) is dissolved in 50 ml of ether and added to a solution of LiAlH4 (0.54 g, 0.014 mole) in 50 ml of ether at such a rate to maintain gentle refluxing. When the addition is complete, the solution is refluxed for one hour. Ethyl acetate (2 ml) is added to destroy excess LiAlH4. The mixture is acidified with 5M HCl. The ether layer is separated, washed 2X with water, and dried over sodium sulfate. The ether solution is concentrated and the residue vacuum distilled to yield trans-2-nonenol.