Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[CH2:49][NH:48][CH2:47]3)[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:48]2[CH2:47][C:46]3[C:50](=[CH:51][CH:52]=[C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]4)[CH:45]=3)[CH2:49]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)c(O)cc1O
Reactant: CN1CCN(c2ccc3c(c2)CNC3)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3c(c2)CN(C(=O)c2cc(Cl)c(O)cc2O)C3)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-chloro-2,4-dihydroxy-benzoic acid (176 mg, 0.93 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (179 mg, 0.93 mmol) then HOBt (126 mg, 0.93 mmol). After 45 minutes, the solution of the activated acid was added to a mixture 5-(4-methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole dihydrochloride (290 mg, 0.78 mmol) and triethylamine (0.28 mL, 2 mmol) then the mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo then the residue was partitioned between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and brine then dried (MgSO4), combined and concentrated. Some insoluble material remained and this was dissolved in 1N hydrochloric acid and methanol then combined with the organic extracts. The pH was adjusted to 14 with solid sodium hydroxide and the mixture allowed to stand overnight. The pH was adjusted to 7 with 1N hydrochloric acid and the resulting precipitate was filtered off then subjected to purification by preparative HPLC to afford the title compound as a red solid. This was converted to its hydrochloride salt by treatment with 4M HCl in dioxane, concentration in vacuo and trituration with ether which gave a brown solid (91 mg, 27%). 1H NMR (DMSO-d6) 11.10 (1H, br. s), 10.50 (1H, br. s), 7.26-7.15 (2H, m), 7.02-6.93 (2H, m), 6.69 (1H, s), 4.72-4.61 (4H, m), 3.78-3.72 (2H, m), 3.45 (2H, br. s), 3.12 (4H, br. s), 2.78 (3H, s). MS: [M+H]+ 386/388.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][CH:23]1[CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH:23]1[CH2:25][CH2:24]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: ICCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCC2CC2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 85.3 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g) is alkylated using (2-iodo-ethyl)-cyclopropane (5.36 g; 27.3 mmol) and K2CO3 (6.30 g; 45.6 mmol) at 55° C. for 12 h. After aqueous work-up the crude material (4.21 g) is de-acetylated in hydrochloric acid (6 N, 30 ml) at reflux. After aqueous work-up 5-amino-1-(2-cyclopropyl-ethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (3.75 g) is obtained and used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[C:10]([C:12]34[CH2:19][CH2:18][C:15]([CH:16]=[CH:17]3)=[CH:14][CH2:13]4)[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[NH2:20][NH2:21].Cl>C(O)C>[NH:20]([C:2]1[N:3]=[C:4]2[C:9](=[C:10]([C:12]34[CH2:19][CH2:18][C:15]([CH:16]=[CH:17]3)=[CH:14][CH2:13]4)[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2)[NH2:21]
Reactant: NN
Reactant: Clc1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Agent: Cl
Solvent: CCO
Product: NNc1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Temperature: 25 °C

Procedure:
6-Chloro-1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine (1.03 g) was treated with anhydrous ethanol (10 mL), anhydrous hydrazine (Aldrich, 4.0 mL) and concentrated HCl (0.4 mL). The reaction mixture was then heated in a screw cap pressure tube at 150° C. until LCMS showed complete conversion to the hydrazine (approx. 96 h). The reaction mixture was cooled to ambient temperature, then concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 6-hydrazino-1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine as a pale yellow solid (0.68 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:20][OH:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][CH2:9][C:10]1([CH:20]=[O:21])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1(COCc2ccccc2)CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
To a solution of (8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol (Reference Example 85) (183 mg, 0.625 mmol) in dimethyl sulfoxide (2.1 mL), 50% sulfur trioxide-pyridine complex (596 mg, 1.87 mmol) and triethylamine (0.522 mL, 3.75 mmol) were added, and the obtained solution was stirred at room temperature for 20 minutes. The reaction was quenched by adding water to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed sequentially with 20% aqueous citric acid solution, saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (172 mg, 0.592 mmol, 95%) as a colorless oily compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH:2]([OH:4])[CH2:3][N:15]1[CH2:20][CH2:19][CH:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:17][CH2:16]1)[CH:6]=[CH:7]2
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Fc1ccc2c(ccn2CC2CO2)c1
Product: OC(CN1CCC(c2c[nH]c3ccccc23)CC1)Cn1ccc2cc(F)ccc21
Yield: 51 %

Procedure:
A methanolic solution of 1-N-glycidyl-5-fluoroindole (0.52 g, 3.0 mmole) from example 1 and 3-(4-piperidinyl)indole (0.6 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as an oil (0.599 g, 50% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a white solid. The product was recrystallized twice from ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (800 mg, 1.54 mmol; Example 4) and morpholine (1.5 eq., 201 mg, 2.31 mmol) were initially charged in dry THF (25 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 89 mg, 0.077 mmol) was added, and the reaction mixture was stirred at RT for 90 min (HPLC control). The reaction mixture was then concentrated and the residue was taken up in ethyl acetate (500 ml). The organic phase was washed with saturated ammonium chloride solution (50 ml), with water (50 ml) and with conc. sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10).
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=[O:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH2:19]([O:18][C:16]([CH2:15][N:4]1[C:3](=[O:13])[CH:2]([CH3:1])[S:6][CH:5]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: CC1SC(c2cccnc2)NC1=O
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 14.5 %

Procedure:
5-Methyl-2-(3-pyridyl)thiazolidin-4-one (10 g, 51.5 mmol) (cis and trans mixture) and ethyl bromoacetate (6.85 ml, 61.8 mmol) were dissolved in dry dimethylformamide (50 ml), and 60% sodium hydride (2.16 g, 54.1 mmol) was added portionwise to the solution at 0° to 10° C. This reaction mixture was kept between those temperatures for 1 hour. The mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, giving the cis-isomer (5.8 g) and the trans-isomer (2.1 g) of the title compound (55% yield).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[OH-].[NH4+]>>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(NC(C)=O)c([N+](=O)[O-])c1)n1ccnc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCCC(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of 11.5 parts of intermediate 9, namely N-[4-[1-(1H-imidazol-1-yl)butyl]2-nitrophenyl]acetamide and 150 parts of a hydrochloric acid solution 3N was stirred for 3 hours at reflux temperature. The reaction mixture was poured into crushed ice and the whole was neutralized with concentrated ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 8.8 parts (88.9%) of 4-[1-(1H-imidazol-1-yl)butyl]-2-nitrobenzenamine as a residue (interm. 10).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(Sc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A PPE (polyphosphate ester) solution (7 mL) was added to a mixture of 4-hydroxybenzoic acid (552 mg, 4 mmol) and 4-mercaptophenol (554 mg, 4.4 mmol). After stirring for 16 h, the solvents were removed by evaporation and the residue was purified by column chromatography (hexane-EtOAc 7:1 to 1:1). 4-Hydroxy-thiobenzoic acid S-(4-hydroxy-phenyl)ester (240 mg, 24%) was obtained as a white solid. MS (ES) m/z: 247.04 (M+1), 167.03, and 122.55. 13C-NMR (DMSO-d6): δ 188.24, 162.85, 158.82, 135.87, 129.59, 127.10, 116.33, 115.72, and 115.34.
Reaction SMILES: ClCl.[N+:3]([C:6]([N+:23]([O-:25])=[O:24])([CH2:9][O:10][CH2:11][O:12][CH2:13][C:14]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:15][OH:16])[CH2:7][OH:8])([O-:5])=[O:4].ClC(SS[C:32]([O:53][CH2:54][C:55]([F:62])([N+:59]([O-:61])=[O:60])[N+:56]([O-:58])=[O:57])([O:43][CH2:44][C:45]([N+:50]([O-:52])=[O:51])([N+:47]([O-:49])=[O:48])[F:46])[O:33][CH2:34][C:35]([N+:40]([O-:42])=[O:41])([N+:37]([O-:39])=[O:38])[F:36])(Cl)Cl>ClCCCl>[F:36][C:35]([N+:37]([O-:39])=[O:38])([N+:40]([O-:42])=[O:41])[CH2:34][O:33][C:32]([O:53][CH2:54][C:55]([N+:56]([O-:58])=[O:57])([N+:59]([O-:61])=[O:60])[F:62])([O:43][CH2:44][C:45]([N+:47]([O-:49])=[O:48])([N+:50]([O-:52])=[O:51])[F:46])[O:16][CH2:15][C:14]([N+:17]([O-:19])=[O:18])([N+:20]([O-:22])=[O:21])[CH2:13][O:12][CH2:11][O:10][CH2:9][C:6]([N+:23]([O-:25])=[O:24])([N+:3]([O-:5])=[O:4])[CH2:7][OH:8]
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])SSC(Cl)(Cl)Cl)[N+](=O)[O-]
Reactant: O=[N+]([O-])C(CO)(COCOCC(CO)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Agent: ClCl
Solvent: ClCCCl
Product: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(COCOCC(CO)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 22 h

Procedure:
Chlorine gas was passed into a solution of 3.78 g (0.011 mol) of 2,2,8,8-tetranitro-4,6-dioxanonane-1,9-diol and 6.53 g (0.01 mol) of tris(2-fluoro-2,2-dinitroethoxy)methyl trichloromethyl disulfide in 20 ml of dry 1,2-dichloroethane at 65° C. for two hours. Heating at 65° C. was continued for 22 hours at which time the solvent was removed and the oily residue was washed with 2×30 ml of hexane. Thin layer chromatography indicated the product was a mixture of the mono-(XI) and the bis-orthocarbonate (XII). The mono-orthocarbonate (XI) was isolated by column chromatography (silica gel 60, methylene chloride-ethyl acetate (90:10) as eluent) as a viscous gummy oil; H-NMR [(CD3)2C=O]: δ 5.20 (d), 4.96 (s), 4.83 (s), 4.68 (s), 4.58 (s), 4.54 (s). IR (film on NaCl plate) 3600 (OH), 1600 (NO2) cm-1.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]=1[I:25].C(ON=O)(C)(C)C>O1CCCC1>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[CH:2]=[C:3]([I:25])[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:5]1
Reactant: Nc1c(I)c(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc(I)c(-c3ccccc3)n2)c(Cl)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)4iodo-3-phenylpyrazole (2.5 g) in tetrahydrofuiran (50 ml) at 65° C. was added dropwise t-butylnitrite (3 g) in tetrahydrofuran (20 ml) over a period of 30 minutes and heating continued for 3 hours then left at room temperature overnight. The reaction mixture was evaporated to an oil which was purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of appropriate fractions, followed by further column chromatography on silica gel eluted with hexane, then hexane containing 5% ethyl acetate and finally hexane containing 10% ethyl acetate. Combination and evaporation of appropriate fractions gave the title compound as a cream solid m.p. 88-89° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:17])=[N:14][C:15]=1[CH3:16]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7](=[S:8])[NH:17][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[C:15]([CH3:16])[N:14]=1)[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: Cc1nc(N)ccc1Br
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Br)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethoxycarbonylisothiocyanat (7.71 g) was added to a stirred solution of 5-bromo-6-methylpyridin-2-amine (10.0 g) in dioxane (90 ml). The mixture was stirred for 2 h at r.t. A white solid precipitated. Hexane (100 ml) was added and the white solid was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>C(OC)(OC)OC>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: Cn1cnc2ccc(Cl)nc21
Reaction time: 3 h
Yield: 2681.7 %

Procedure:
To a solution of 6-chloro-N2-methylpyridine-2,3-diamine (300 mg, 1.9 mmol) in HC(OMe)3 (10 mL) was added TsOH (10 mg) at 22° C. The mixture was stirred for 3 h under reflux until TLC (PE: EA=3:1) showed that the reaction was complete. The mixture was concentrated to get the crude material which was purified by using column chromatography on silica gel to give the desired product (261 mg, 81.6%) as an oil. LCMS (m/z): 168.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>[Fe].CCO.O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccc(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Yield: 0.1 %

Procedure:
A solution of 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole (0.142 g, 0.491 mmol), ammonium chloride (0.013 g, 0.245 mmol) in 4:1 v/v EtOH/water (5 mL) was treated with iron (0.274 g, 4.91 mmol) and refluxed for 2 hours. The mixture was concentrated and the residue taken in EtOAc/water, filtered through glass fiber filter paper and concentrated again to provide 1-(2,4-difluorobenzyl)-1H-indazol-4-amine (0.096 mg, 75% yield) as an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16].[OH-].[Na+]>CN(C)C=O.O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(F)c(-c2cccs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccc(F)c(-c3cccs3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
4-Fluoro-3-thiophen-2-yl-benzaldehyde (1.0 g, 4.85 mmol, from Ex-20A) and 4-acetylbenzoic acid (0.80 g, 4.87 mmol) were dissolved in dimethylformamide (55 mL). Sodium hydroxide solution (5 N, 3.88 mL) was added in one portion, and the mixture was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethanol provided 0.90 g (53%) of the title compound as a solid, m.p. 242–244° C. 1H-NMR (300 MHz, d6-DMSO) δ 13.31 (bs, 1H), 8.32 (dd, 1H, J=8.2 and 2.0 Hz), 8.24 (d, 2H, J=8.2 Hz), 8.07 (d, 2H, J=7.9 Hz), 7.98 (d, 1H, J=16.1 Hz), 7.92 (m, 1H), 7.80 (d, 1H, J=16.1 Hz), 7.69–7.73 (m, 2H), 7.41 (dd, 1H, 10.8 and 9.2 Hz), 7.20 (m, 1H). MS m/z=352 ([M]+, 50%), 343 (100%). HRMS (EI) Calcd. for C20H13FO3S: 352.0569. Found: 352.0571.
Reaction SMILES: O[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4](=[O:13])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>C(O)C>[O:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]1[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:2]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C1=CC(c2ccccc2)Oc2ccccc21
Reaction time: 2 h
Yield: 75.4 %

Procedure:
2'-Hydroxychalcone (9.0 g) was stirred with ethanol (100 ml) at room temperature whilst sodium borohydride (3.05 g) was added in small portions. After 2 hr. stirring the colourless solution was evaporated to dryness and acetic acid (100 ml) added. Toluene sulphonic acid (1.0 g) was added and the solution was heated on the steam bath for 30 min. The solution was diluted with water and extracted with toluene. The extract was washed with saturated sodium bicarbonate solution, dried over magnesium sulphate, and evaporated. The residue was chromatographed on neutral alumina to yield flav-3-ene (6.3 g) as an oil, identified by its n.m.r. spectrum. The multiplet at 5.8 p.p.m. is characteristic of flav-3-enes.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:23][O:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Solvent: CO
Solvent: O
Product: COC(C)(C)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one (83.8 mg, 0.30 mmol) in methanol (1 ml) is added toluene-4-sulfonic acid monohydrate (5.2 mg, 0.030 mmol). The reaction mixture is stirred for 5 days at ambient temperature. The reaction mixture, a white suspension, is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 3-[4-(1-methoxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one as white crystals; HPLC/MS 2.66 min (B), [M+H] 294;
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([CH3:31])[CH:23]=1>C(O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH3:31])=[O:30])[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: COc1ccc(N=C=O)c(C)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)NC2C3CC4CC(C3)CC2C4)c(C)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 2.5 g (13.3 mmol) of 2-adamantylamine hydrochloride, 1.84 ml (13.3 mmol) of triethylamine in 50 ml of ethanol was heated under reflux. Then 1.94 ml (13.3 mmol) of 4-methoxy-2-methylphenylisocyanate was added and the mixture was stirred under reflux for 2 h. After cooling at room temperature the precipitate was filtered, washed with ethanol and dried under vacuum to give 4.2 g (61%) a white solid.