Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]1[C:17]2=[CH:18][NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:15]([C:16]=32)[C:14](=[O:24])[NH:13][CH2:12]1)C)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:1][NH:8][CH2:10][CH:11]1[C:17]2=[CH:18][NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:15]([C:16]=32)[C:14](=[O:24])[NH:13][CH2:12]1
Reactant: CN(Cc1ccccc1)CC1CNC(=O)c2cccc3[nH]cc1c23
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNCC1CNC(=O)c2cccc3[nH]cc1c23
Yield: 52.7 %

Procedure:
2.38 g of 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (see Example 3 for preparation) were dissolved in 150 ml of methanol. A spatula tip of a palladium/carbon catalyst (10%) was added to the solution under a stream of nitrogen. The mixture was subsequently hydrogenated in an autoclave under a hydrogen pressure of 3.5 bar at a temperature of 50° C. while stirring. After 3 hours the hydrogen was discharged, the reaction mixture was flushed with nitrogen and the catalyst was filtered out. The remaining solution was evaporated and the oily crude product remaining as residue was purified by low pressure chromatography on silica gel using methanol/25% strength aqueous ammonia solution 96:4 as eluent. 0.9 g of 3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole was obtained as a foam-like product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[N:6][CH:7]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.C(OCC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:18]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[N:17][C:9]=1[O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccnc1Oc1cncc(Cl)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)c1cccnc1Oc1cncc(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A 15 ml flask was charged with 2-(5-chloro-pyridin-3-yloxy)-nicotinic acid (0.056 grams, 0.22 mmole), benzyl alcohol (0.052 grams, 0.44 mmole), 4-DMAP (˜3 mg), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.048 grams, 0.25 mmole), diethyl ether (4 ml) and pyridine (1 ml) and stirred at room temperature. After 1 hour the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 9/1 ethyl acetate/hexane to give 0.060 g of the title compound as a colorless oil. Anal. calcd. for C18H13ClN2O3: M.S. m/z [M+] 341; 1H NMR (CD3OD) d 4.58 (s, 2H), 7.45(m, 7H), 7.71 (s, 1H), 8.28 (m, 2H), 8.38 (m, 2H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>CC(N(C)C)=O>[CH:15]1([CH2:18][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)[CH2:17][CH2:16]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(CC2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 20 g. isatoic anhydride in 200 ml. dimethylacetamide is added under nitrogen with stirring sodium hydride obtained from 6 g. of a 57% dispersion in mineral oil, while maintaining the temperature below 25°C. The resulting mixture is stirred at 25°C. for 1 hour and to it is added 17 g. cyclopropylmethylbromide. The mixture is then stirred at room temperature for about 20 hours. It is then poured on water. The mixture is stirred for 15 minutes, the solids collected by filtration, washed with several portions of water and then three times with 0.7 kg. of diethylether. The washed solids are dried to obtain N-(cyclopropylmethyl)isatoic anhydride, m.p. 118°-121°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1/[CH:13]=[CH:14]/[C:15]([O:17]CC)=O>Cl.O1CCOCC1>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:13]=[CH:14][C:15](=[O:17])[NH:1]2)=[CH:4][C:5]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CCOC(=O)/C=C/c1cc(C(F)(F)F)c(F)cc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(C(F)(F)F)c(F)cc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-4-fluoro-5-(trifluoromethyl)phenyl)acrylate in 4N HCl in dioxane (10 mL) was added concentrated HCl (2 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time (min)=1.887, method [1], MS (ESI) 232.0 (M+H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCCCCc1ccc(O)cc1
Product: CCCCCc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-pentylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (4%, light brown oil). HPLC-MS: m/z=298.2 (M+1); Rt: 5.61 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Cl>C(Cl)CCl.CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: ClBr
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 2,6-di-tert-butylphenol (2.06 g, 10 mmol) in EDC (50 mL) in a 200-mL round bottom flask, was added the stabilized BrCl brominating reagent (12 mL, about 11 mmol) dropwise, with stirring at room temperature. Initially, the orange reddish color of the reagent disappeared quickly. The color from the last 1 mL persisted for several minutes. The reaction mixture was allowed to stand for 30 minutes before being quenched with a few drops of sodium sulfite solution. After phase separation, it was diluted with EDC (50 mL), washed with water (100 mL) and dried (Na2SO4). The organic layer was concentrated under reduced pressure to afford a glue-like material. The material was redissolved in ether (10 mL) and after solvent removal, a crystalline solid 4-bromo-2,6-di-tert-butylphenol product (2.63 g, 92% recovered yield) was obtained in high purity (>98% by GC).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:23]>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])=[CH:17][C:16]=1[CH3:23]
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C=O)cc1C
Solvent: CCO
Product: COc1ccc(C=NN2C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Yield: 85 %

Procedure:
N-aminophthalimide (1.62 g) and 4-methoxy-3-methylbenzaldehyde (1.50 g) were added to ethanol (20 ml), the mixture was stirred under heat reflux overnight. The mixture was allowed to cool to a room temperature, and then the precipitate was separated by filtration, washed with ethanol, and dried under a reduced pressure to give the title compound (2.50 g, 84%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCO)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
4-(2-Hydroxyethyl)phenol (2 g, 14.48 mmol) and methyl 2-(bromomethyl)benzoate (3.48 g, 15.20 mmol) were dissolved in acetonitrile (20 ml). Potassium carbonate anhydrous (4.0 g, 28.95 mmol) was added. After stirring at 60° C. for three hours PS-trisamine was added (0.2 eq) and the mixture was stirred overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 3.732 g of methyl 2-{[4-(2-hydroxyethyl)phenoxy]methyl}benzoate (yield 90%).
Reaction SMILES: [OH:1][C@:2]1([CH2:30][OH:31])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[OH:1][C@:2]1([CH2:30][O:31][C:39](=[O:40])[N:38]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(CO)C2)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(COC(=O)N(c1ccccc1)c1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
A mixture of (2R)-2-hydroxy-2-hydroxymethyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g) and N,N-diphenylcarbamoyl chloride (3 g) in pyridine (15 ml) was stirred at 100° C. for 12 hours, cooled to room temperature, and partitioned between ethyl acetate and 1N-HCl. The organic layer was washed with water, sat. NaHO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (2R)-2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: Cn1ncc(Br)c1C=O
Product: Cn1ncc(Br)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 4-bromo-2-methyl-2H-pyrazole-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.Cl.[CH3:18][C:19](C)=[O:20].C(Cl)(=O)C>C(N(CC)CC)C>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:20])[CH3:18]
Reactant: Nc1ccccc1N1CCc2ccccc21
Reactant: CC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred slurry, under N2, of 9.96 g of 1-(2-amino-phenyl)indoline.HCl and 300 ml of dry acetone is treated with 10.1 g of triethylamine over a 10 minute period. After cooling to 0°-5° C., 4.70 g of acetyl chloride is added dropwise over 0.5 hour. The mixture is stirred 18 hours at ambient temperature, then filtered. The filtrate is diluted with 100 ml of water and concentrated. When all the acetone is removed, the residue is filtered off, washed well with water, and dried to afford 1-(2-acetamidophenyl)indoline, m.p. 125°-128° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C1(=O)O[CH2:10][CH2:9][O:8]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][CH2:9][OH:8]
Reactant: O=C1OCCO1
Reactant: OCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F
Temperature: 100 °C
Reaction time: 36 h
Yield: 71 %

Procedure:
2,2,2-Trifluoroethanol (24.0 g), triethylamine (24.0 g), tetrabutylammonium iodide (1.7 g), and ethylene carbonate (30.5 g) were mixed, and the mixture was heated at 100° C. (internal temperature) and stirred for 36 hours. The reaction mixture was concentrated under reduced pressure at room temperature, and then subjected by distillation (67° C., 30 mmHg), whereby 2-(2,2,2-trifluoroethoxy)ethanol was obtained (24.7 g, yield: 71%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].C([BH3-])#N.[Na+]>CO>[C@@H:16]([NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@H](C)N
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)NCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 69.2 %

Procedure:
4-Phenoxybenzaldehyde (8.13 g, 41 mmol) and (S)-sec-butylamine (3 g, 41 mmol) were dissolved in methanol (137 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (2.58 g) was added, and stirring was continued for 18 hours. The solvent was removed, and the residue was suspended in ether, washed with brine and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 7.24 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=CCCCOc1nc2c(cc1Br)CCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(Br)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (1.11 g, approx. 3.54 mmol, crude) in DCE (17 mL) was added 1-naphthalen-1-yl-piperazine hydrochloride (0.882 g, 3.54 mmol) followed by Et3N (1.0 mL, 7.1 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (1.05 g, 4.96 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as an off-white foam (1.37 g, 2.69 mmol, 76%). The HCl salt was formed by dissolving the title compound (138 mg, 0.27 mmol) in Et2O/CH2Cl2 followed by the addition of 1N HCl in Et2O (0.3 mL). The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (125 mg). MS: APCI: M+1: 509.1, 511.1 (Exact Mass: 508.15).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1/[CH:6]=[CH:7]/[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1.C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1/[CH:6]=[CH:7]/[CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:23]1=[O:24])([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccccc1/C=C/CNCCNc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1N(C/C=C/c2ccccc2[N+](=O)[O-])CCN1c1ccncc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 56.8 %

Procedure:
To a solution of 2.33 g of (E)-N-(2-nitrocinnamyl)-N'-(4-pyridyl)ethylenediamine dissovled in a mixture of 50 ml of tetrahydrofuran and 50 ml of chloroform was added 1.52 g of carbonyldiimidazole at 0° C. The mixture was stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol=3:1) and recrystallized from a mixture of isopropanol and methanol to give 1.44 g of (E)-1-(2-nitrocinnamyl)-3-(4-pyridyl)-2-imidazolidinone.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>CC(C)=O>[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:4](=[O:5])[C:3]1[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=1[C:1]([OH:6])=[O:11]
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(C)=O
Product: O=C(O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 0.08 h

Procedure:
3,4,5,6-tetrahydrophthalic anhydride (7.7 g) and 2-fluoro-4-chloroaniline (7.2 g) were added to acetone (50 ml) and, after stirring at 50°-55° C. for 5 minutes, the reaction mixture was concentrated under reduced pressure. The resultant crystals were washed with n-hexane. Yield 13.2 g; m.p. 92°-94° C.
Reaction SMILES: [O:1]=[C:2]([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:9]#[N:10]>>[C:9]([C:2]([OH:1])([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5])#[N:10]
Reactant: O=C(O)CC(=O)CCl
Reactant: C#N
Product: N#CC(O)(CCl)CC(=O)O

Procedure:
reacting 3-oxo-4-chlorobutyric acid with HCN in an aqueous system to form 3-cyano-3-hydroxy-4-chlorobutyric acid,
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:29]([NH2:32])(=[O:31])=[O:30])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCCNS(N)(=O)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 76.6 %

Procedure:
A solution of 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.82 g) and sulphamide (0.96 g) in dioxane (30 ml) was heated under reflux for 70 minutes and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.75 g), m.p. 150°-152° C. Found: C, 49.33; H, 5.35; N, 8.93. C20H26ClN3O7S requires C, 49.23; H, 5.37; N, 8.61%.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:17][C:18]1[S:19][C:20](Cl)=[N:21][N:22]=1>C(O)C>[NH2:17][C:18]1[S:19][C:20]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:21][N:22]=1
Reactant: CCCCNCCCC
Reactant: Nc1nnc(Cl)s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCN(CCCC)c1nnc(N)s1

Procedure:
28 parts of dibutylamine and 25 parts of triethylamine are added to 27 parts of 2-amino-5-chloro-1,3,4-thiadiazole in 200 parts of ethanol. The reaction mixture is heated under reflux for 2 hours and then concentrated to dryness. The residue is suspended in 250 ml of water and filtered. The 2-amino-5-dibutylamino-1,3,4-thiadiazole obtained in this manner can be recrystallised from ethanol/water.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4]C.C(=O)([O-])[O-].[K+].[K+].[OH:16][N:17]=[C:18](Br)[Br:19]>ClCCl>[CH2:8]([O:7][C:1]([C:2]1[C:18]([Br:19])=[N:17][O:16][C:3]=1[CH3:4])=[O:6])[CH3:9]
Reactant: ON=C(Br)Br
Reactant: CCC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1c(Br)noc1C
Temperature: 25 °C
Yield: 114 %

Procedure:
To a solution of ethyl 2-pentynoate (16.09 mL, 138 mmol) in dichloromethane (80 mL) was added potassium carbonate (20.65 g, 147.9 mmol) and then a solution of hydroxycarbonimidic dibromide (20.0 g, 98.6 mmol) in dichloromethane (100 mL) was added. The reaction mixture was stirred at room temperature over night. The solvent was then removed and purification by filtration (silica, dichloromethane then ethyl acetate) afforded the title compound (26.3 g, 88%) as a light yellow oil. MS: m/e=234.0 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:15][CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][CH:16]([CH3:18])[CH2:17][N:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]1=[O:1]
Reactant: COC(=O)c1ccnc(O)c1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(CC(C)C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a solution of methyl 2-hydroxy-4-pyridinecarboxylate (D26; 1.02 g, 6.66 mmol) in N,N-dimethylformamide (20 ml) was added sodium hydride (60%; 0.293 g, 7.33 mmol). The resulting solution was stirred at room temperature for 15 mins. 1-Bromo-2-methylpropane (0.87 ml, 7.99 mmol) was then added and the mixture was stirred at 80° C. for 2 hrs. The reaction was quenched with methanol and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water, the organic layer dried over magnesium sulphate and concentrated under vacuum. The crude material was purified by chromatography on silica, eluting with 50-80% ethyl acetate in cyclohexane gave the title compound as a light blue solid (450 mg). MS: m/z 210 [MH+]. O-alkylated material was also isolated.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>CN(C=O)C.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C1CSCCN1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCSCC3)n2n1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 99 mg, 0.287 mmol) and thiomorpholine (91 mg, 0.861 mmol) in DMF (1.11 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with methanol and then purified by preparatory HPLC (35-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (26.9 mg, 39%). Melting point (229.1-229.2° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H), 2.38 (s, 3 H), 2.75-2.90 (m, 4 H), 4.02 (dt, J=4.67, 2.46 Hz, 4 H), 6.16 (s, 1 H), 7.35 (s, 1 H), 7.60 (d, J=8.34 Hz, 2 H), 7.99 (d, J=8.34 Hz, 2 H), 10.86 (s, 1 H); ESI-MS: m/z 412.2 (M+H)+.