Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1.[NH2:23][C:24]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].C(N(CC)CC)C>C(#N)C>[CH3:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:24]=1[NH:23][C:8]([C:6]1[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of the title compound of Example 3, Step B (0.54 g, 1.1 mmol), the title compound from Example 1, Step B (0.44 g, 2.4 mmol) and BOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g, 2.1 mmol) in acetonitrile (13 mL) was treated with triethylamine (0.9 mL). The mixture was shaken in a closed scintillation vial for 18 h. The reaction was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid. The ethyl acetate layer was washed successively with 1N hydrochloric acid (50 mL), 1N sodium hydroxide (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The title compound (0.43 g), a compound of the present invention, was isolated as a white solid. m.p. 227-230° C.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15](=O)[CH2:16][CH3:17])=[N:3]1.OS(O)(=O)=O.O.[NH2:26]N.C([O-])(O)=O.[Na+]>C(O)(=O)C.O.C(O)C>[CH2:16]([C:15]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([O:13][CH3:14])[CH:9]=2)[C:4](=[O:5])[NH:3][N:26]=1)[CH3:17]
Reactant: CCC(=O)c1cc(OC)ccc1C1=NC(C)(C)CO1
Reactant: NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCc1n[nH]c(=O)c2ccc(OC)cc12
Temperature: 80 °C
Yield: 41.3 %

Procedure:
A solution of 1-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-propan-1-one (6.4 g, 15.9 mmoles), prepared as described in example 8, in 110 ml of a mixture of water (10 ml), ethanol (100 ml) and concentrated H2SO4 (8 ml) up to 200 ml with ethanol, was stirred under N2 and reflux for 20 hours, then concentrated, taken up in water and extracted more times with ethyl ether. The organic phases were washed with water, anhydrified and brought to dryness to give an oil which was dissolved in acetic acid and added, at 15° C., with hydrazine monohydrate (1.56 g, 31.2 mmoles) in acetic acid (10 ml). At the end of the addition, the mixture was heated to 80° C. and, after 20 hours, brought to small volume, taken up in water, neutralised with NaHCO3 and extracted more times with CHCl3. The organic phases were anhydrified and brought to dryness to give a residue, which was flash chromatographed (eluent: hexane/ethyl acetate 9:1, then 7:3). There were thus obtained 1.34 g of the title compound (yield: 44%). m.p.: 230-235° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCN(CC1)CC2>CCC(C)=O>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:5]2[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([NH:1][C:30](=[O:31])[NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][CH:4]=2)[N:14]=1
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Reactant: O=C=Nc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CCC(C)=O
Product: COC(=O)c1nc(NC(=O)Nc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 71.1 %

Procedure:
2 g (6.5 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate, 0.77 g (7.15 mmol) of phenyl isocyanate and a catalytic amount of crystals of 1,4-diazabicyclo-[2.2.2]-octane were added to 50 ml of MEK, and the mixture was stirred and refluxed for 4 hours. After completion of the reaction, the product was filtered and washed with MEK to obtain the desired product as colorless transparent crystals.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](O)=[O:32].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.O>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:32]
Reactant: O=C(O)Cc1ccccc1F
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2ccccc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine-2HCl (70.6 mg, 0.209 mmol), (2-fluorophenyl)acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base (0.146 mL, 0.836 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford 5-{1-[(2-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (73 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.26 (t, J=8.72 Hz, 2H), 3.73 (s, 3H), 3.93 (s, 2H), 4.28 (t, J=8.46 Hz, 2H), 7.19 (d, J=7.58 Hz, 3H), 7.26 (s, 1H), 7.30-7.38 (m, 3H), 8.09 (d, J=8.34 Hz, 1H), 8.14 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].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.CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][CH:27]([CH3:29])[CH3:28])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 48) (67 mg, 0.163 mmol) and N1,N1-dimethylethane-1,2-diamine (28.8 mg, 0.326 mmol) in DMF (2 mL) were added HATU (93 mg, 0.245 mmol) and DIPEA (0.086 mL, 0.490 mmol). The resulting mixture was stirred at room temperature for 1 h, then hydrolyzed by adding water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated under reduced pressure to give isopropyl ((2S,4R)-1-acetyl-6-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (35 mg, 41%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.65 min, MH+=481.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11](OCC)=[O:12])[O:9][C:8]([CH2:17][CH3:18])([CH3:16])[O:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH2:17]([C:8]1([CH3:16])[O:7][CH:6]([CH2:4][OH:3])[CH:10]([CH2:11][OH:12])[O:9]1)[CH3:18]
Reactant: CCOC(=O)C1OC(C)(CC)OC1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCC1(C)OC(CO)C(CO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A solution of 4,5-diethoxycarbonyl-2-ethyl-2-methyl-1,3-dioxolane (13.68 g, 52.6 mmol) in dry ether (80 ml) was added dropwise over 30 min to a suspension of lithiumaluminiumhydride (2.4 g, 63.2 mmol) in dry ether (100 ml) and the mixture was refluxed under nitrogen for 2 h then stirred at room temperature overnight then refluxed for 2 further hours. On cooling, water (2.5 ml), sodium hydroxide (4N, 2.5 ml) and water (25 ml) were sequentially added cautiously down the condenser. The supernatant was decanted off and the residue was triturated with ether (2×100 ml). The combined ether layers were dried over sodium sulfate, filtered and evaporated to dryness. The residue was distilled under high vacuum (approx. 2 mm, 160 deg.) to give the title compound as a clear oil (5.41 g, 58%).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[C:4]([S:32]CC2C=CC(OC)=CC=2)=[C:5]([C:9]([CH2:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[C:10]([NH:12][C@H:13]([C:23]([NH:25][CH3:26])=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[F:42][C:2]([F:1])([F:43])[C:3]1[C:4]([SH:32])=[C:5]([C:9]([CH2:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[C:10]([NH:12][C@H:13]([C:23]([NH:25][CH3:26])=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(C)(CC(C)C)c1cccc(C(F)(F)F)c1SCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(C)(CC(C)C)c1cccc(C(F)(F)F)c1S
Temperature: 0 °C

Procedure:
An ice-cooled solution of 3-trifluoromethyl-2-(4-methoxybenzylthio)-N-[2-(4-methoxyphenyl)-1-(S)-(methylaminocarbonyl)ethyl]-α-(2-methylpropyl)phenylpropanamide (D13) (308 mg, 0.5 mmol) and anisole (0.1 ml) in trifluoroacetic acid (5 ml) was treated with mercuric acetate (160 mg, 0.5 mmol). After 15 min the solvent was evaporated and the residue was azeotroped dry with toluene. The residual oil was triturated with ether to give a white solid, which was separated and washed with a little ether. The solid was dissolved in dry DMF (3 ml) and the solution was purged with nitrogen. Hydrogen sulphide gas was bubbled through the solution for 3 min. The resulting black suspension was purged with nitrogen for 30 min, then the solvent was evaporated in vacuo. Column chromatography (10 g silica) eluting with ethyl acetate and trituration of the product with pentane gave the title compound as a 1:1 mixture of diastereoisomers (88 mg, 35%), mp 88°-102° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[C:7](OC)[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1cccc2c(NCc3ccccc3C)cc(CCl)nc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc(NCc2ccccc2C)c2ccccc2n1

Procedure:
800 mg (=2.2 mmol) of 2-chloromethyl-8-methoxy-4(2-methylbenz-ylamino)quinoline hydrochloride were refluxed with 1.2 g (=22 mmol) of sodium methylate in 30 ml of absolute methanol for 5 hours The mixture was concentrated in a rotary evaporator, ethyl acetate was added, and the mixture was extracted several times with K2CO3 solution. The residue after drying over Na2SO4 and removal of the solvent was recrystallized from ethanol 200 mg (=28%) of 8-methoxy..2-methoxymethyl-4-(2-methylbenzylamino)quinoline of melting point 194-195° C. were obtained
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](Cl)([Cl:9])=[O:8]>C(Cl)Cl>[N:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(Cl)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Piperidine (0.3 g, 3.52 mmol) was added to a mixture of phosgene (4.7 ml of 20% phosgene in toluene solution, 8.81 mmol) in methylene chloride (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was evaporated in vacuo. The residue was suspended in ether, filtered and the eluents were condensed to obtain a yellow oil. Purification by flash column chromatography (silica gel, 0-20% ethyl acetate/hexane) gave 0.162 g of the title product. IR (film) 1738.9 cm−1.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Cc1ccc2nc(Br)sc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3ccc(C)cc3s2)c(Cl)c1
Yield: 25.6 %

Procedure:
In xylene (10 ml), 2-bromo-6-methylbenzothiazole (703 mg, 3.08 mmol), methyl 4-amino-3-chlorophenylacetate (615 mg, 3.08 mmol), and pyridinium p-toluenesulfonate (PPTS) (232 mg, 0.92 mmol) were heated under reflux for 10 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (3-chloro-4-(6-methyl-2-benzothiazolyl)aminophenyl)acetate (274 mg, 26%) was obtained as a pale yellow solid.
Reaction SMILES: O=S1(=O)CCCN1C1C=CC(C2N(CC)C3C(C=2C#N)=CC=C(O)C=3)=CC=1.C([O-])([O-])=O.[K+].[K+].IC(C)C.[O:38]=[S:39]1(=[O:67])[CH2:43][CH2:42][CH2:41][N:40]1[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:51]([CH2:65][CH3:66])[C:52]3[C:57]([C:58]=2[C:59]#[N:60])=[CH:56][CH:55]=[C:54]([O:61][CH:62](C)C)[CH:53]=3)=[CH:46][CH:45]=1>CCOC(C)=O.C(Cl)Cl.C(C(C)=O)C>[O:67]=[S:39]1(=[O:38])[CH2:43][CH2:42][CH2:41][N:40]1[C:44]1[CH:45]=[CH:46][C:47]([C:50]2[N:51]([CH2:65][CH3:66])[C:52]3[C:57]([C:58]=2[C:59]#[N:60])=[CH:56][CH:55]=[C:54]([O:61][CH3:62])[CH:53]=3)=[CH:48][CH:49]=1
Reactant: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OC(C)C)cc21
Agent: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(C)I
Product: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21

Procedure:
Following the procedure in example 1B step B, 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile, K2CO3, 2-iodopropane and methyl ethyl ketone are heated at reflux to give, after flash chromatography (EtOAc/CH2Cl2, 0-2%), 61% of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-isopropoxy-1H-indole-3-carbonitrile as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][O-:17].[Na+]>CO.C(OCC)(=O)C>[CH3:16][O:17][C:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OC/C=C/c1cc2ccccc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nc2ccccc2cc1/C=C/CO
Yield: 80 %

Procedure:
A mixture of (E)-3-(2-chloro-3-quinolinyl)-2-propen-1-ol (5.74 g) and sodium methoxide (28% in methanol; 10 ml) in MeOH (30 ml) was refluxed for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was washed with cyclohexane-i-Pr2O to give the titled compound (4.50 g; 80%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]([CH3:19])[CH3:17])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and dimethylamine in ethanol. EI-MS m/e (%): 229 (M+, 49), 228 ([M—H]+, 100), 214 (3)8), 200 (48), 44 (44).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[N:30]1([CH2:35][CH2:36]O)[CH:34]=[CH:33][N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:36][CH2:35][N:30]5[CH:34]=[CH:33][N:32]=[CH:31]5)[C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCCn1ccnc1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCn1ccnc1

Procedure:
5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-imidazol-1-ylethyl)thiazolidine-2,4-dione was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and 2-imidazol-1-ylethanol following General Procedure J.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].I[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO.O>[CH3:11][CH:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH3:12]
Reactant: OCc1ccccn1
Reactant: CC(C)I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
In a closed stainless steel tube were heated pyridine-2-methanol (3.27 g, 30 mmol) and 2-iodopropane (3.59 ml, 36 mmol) at 120° C. for 20 hours. A reaction product was dissolved in a methanol-water (10:1) mixture 23 ml) followed by addition of sodium borohydride (1.14 g, 30 mmol). After stirring at room temperature for 3 hours, a reaction solution was concentrated to dryness. To the residue was added water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel (SiO2 : 90 g, CHCl3) to give 0.61 g of a product (yield 13%). The substance was then subjected to catalytic hydrogenation (2.7 kg/cm2, 1 hour) at room temperature in ethanol (20 ml) using platinum oxide (0.07 g) as a catalyst. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 0.58 g of the title compound.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)=O)=CC=1[N+]([O-])=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[OH:33])=[CH:28][C:27]=1[N+:46]([O-:48])=[O:47].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:34]2[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=2)=[O:33])=[CH:28][C:27]=1[N+:46]([O-:48])=[O:47]
Reactant: COc1ccc(C(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: COc1ccc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: c1cc[nH+]cc1
Product: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Yield: 54.2 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone using (4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.4 g, 6.9 mmol) and pyridinium chlorochromate (2.2 g, 10.3 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 95:5) to afford (4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1.3 g, 55%) as a white solid: 1H NMR (CDCl3) δ 8.34 (d, J=2 Hz, 1H), 8.10-8.06 (dd, J=2, 8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.01 (s, 2H), 4.07 (s, 3H), 3.95 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:13][CH:12]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:11]([C:19]([OH:21])=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C=O)C>[C:1]1([CH:7]([N:9]2[CH2:13][CH:12]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:11]([C:19]([Cl:25])=[O:21])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CC(C(=O)O)C(c2ccsc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CC(C(=O)Cl)C(c2ccsc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The product from step c) (1064 mg, 3.53 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0° C. under N2 atmosphere and oxalyl chloride (1345 mg, 10.59 mmol) was added, followed by 2 drops of DMF. The reaction was stirred at 0° C. for 15 minutes and was allowed to come to room temperature. The reaction mixture was stirred for 1.5 hours and was evaporated to dryness to give the subtitle compound as a solid. MS calculated for C17H18ClNOS +H: 320, observed as methyl ester [dissolved in methanol]+H: 316.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[C:22]([CH3:29])[C:8]=1[O:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>CO>[CH3:6][C:7]1[C:8]([O:9][C:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:22]([CH3:29])[CH:23]=[CH:24][C:25]=1[NH2:26]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1Oc1ncccc1-c1ccncn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(N)c(C)c1Oc1ncccc1-c1ccncn1
Reaction time: 0.08 h

Procedure:
Added tin(II) chloride dihydrate (6.13 g, 27.1 mmol) to a stirring solution/suspension of 4-(2-(2,6-dimethyl-3-nitrophenoxy)pyridin-3-yl)pyrimidine (1.75 g, 5.43 mmol) in methanol (20.0 ml). Heated reaction mixture to 65° C. for 1.25 hours. Filtered hot suspension through Celite which was washed with 20 mL MeOH and 200 mL EtOAc. The organic solution was then extracted with 3×100 1N HCl. The acidic aqueous phase was then basified with 5N NaOH and allowed to stand for 5 minutes. The aqueous phase was then extracted with 3×150 mL portions of CHCl3 which was collected as a bright red-orange solution, dried over sodium sulfate and concentrated in vacuo to afford a brown solid. This was purified by column chromatography (10-100% (2.0 M NH3 in MeOH) in dichloromethane) and concentrated to afford 2,4-dimethyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine as a bright red-orange solid. MS m/z=293 (M+H)+. Calc'd for C17H16N4O: 292.34.