Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1>CCOCC>[F:7][C:8]([F:23])([F:24])[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: N#CC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To lithium aluminium hydride (379 mg, 10 mmol) in Et2O (10 mL) was added dropwise a solution of 1-(4-(trifluoromethoxy)phenyl)cyclopentanecarbonitrile (905 mg, 4 mmol) in Et2O (5 mL) at 0° C. The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 16 h and then quenched with saturated sodium sulfate solution (3 mL) and extracted with Et2O. The organic layer was dried with sodium sulfate and evaporated in vacuo to give (1-(4-(trifluoromethoxy)phenyl)cyclopentyl)methanamine as an oil (810 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=1[F:21])=[S:9])=[O:6].[CH3:23]C([O-])(C)C.[Na+].IC.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5](/[N:7]=[C:8](/[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=1[F:21])\[S:9][CH3:23])=[O:6]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CC(=O)NC(=S)Nc1cccc(C(F)(F)F)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)/N=C(/Nc1cccc(C(F)(F)F)c1F)SC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
An ice-cooled solution of intermediate D19 (17.1 g) in THF (450 ml) was stirred under an atmosphere of N2. NaOtBu (1 eq) was added and after 30 minutes a solution of iodomethane (3.15 ml) in THF was added dropwise. After another 30 minutes an additional NaOtBu (1 eq) was added and the contents stirred at ˜0° C. When the reaction was completed after 45 minutes, a saturated solution of NH4Cl was added and the reaction was diluted with EtOAc. The phases were separated and the aqueous phase extracted with EtOAc (×2). The combined organic extracts were washed with brine, then dried (Na2SO4). Filtration and concentration under reduced pressure gave the crude material as an amber oil. Yield: 17.2 g of intermediate D20 (59%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(Cl)Cl>CN(C=O)C>[Si:20]([O:10][CH2:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCc1ccnc(Cl)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
A mixture of (2-chloro-3-fluoropyridin-4-yl)-methanol (200 mg, 1.24 mmol), imidazole (253 mg, 3.72 mmol) and tert-butyldimethylchlorosilane (373 mg, 2.48 mmol) in DMF was stirred at room temperature for 2 hours. Methylene chloride was then added to the reaction solution, and the solution was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (31.9 mg, 93%).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)(N)C(C)(C)N.[CH2:34](Br)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].P(=O)(O)(O)O>O1CCCC1.CCCCCC>[CH3:25][O:24][C:14]1[C:15]([CH3:23])=[C:16]([CH3:22])[C:17]([O:20][CH3:21])=[C:18]([CH3:19])[C:13]=1[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCBr
Reactant: COc1c(C)c(C)c(OC)c(Cc2ccccc2)c1C
Agent: CC(C)(N)C(C)(C)N
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC(c1ccccc1)c1c(C)c(OC)c(C)c(C)c1OC
Reaction time: 0.42 h
Yield: 77.3 %

Procedure:
A 3.1 ml (5.0 mmole) portion of n-butyllithium.hexane solution was added dropwise to 1.35 g (5.0 mmole) of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene and 0.83 ml (5×1.1 mmole) of 1,1,2,2-tetramethylethylenediamine dissolved in anhydrous tetrahydrofuran (15 ml), under an atmosphere of argon at 50° C. over the period of 5 miniutes, followed by stirring at 50° to 55° C. for 25 minutes. Then, a solution of 0.83 g (5.0 mmole) of n-hexyl bromide in tetrahydrofuran (5 ml) was added dropwise to the mixed solution over the period of 5 minutes, followed by stirring at 50° C. for further 10 minutes. The reaction solution was cooled with ice and made acid by adding a 10% aqueous phosphoric acid solution, and the product was extracted with isopropyl ether. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to effect purification (elution with hexane/isopropyl ether) to thereby give 1.37 g (77%) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptane. Its typical physical properties and nuclear magnetic resonance specrum data are shown in Table 14.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([O:19]C)=[O:18])[CH2:8][CH2:7][C@@H:6]([N:9]([CH3:16])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2].C1COCC1.CO.O[Li].O>O>[CH:1]([C@:4]1([C:17]([OH:19])=[O:18])[CH2:8][CH2:7][C@@H:6]([N:9]([CH3:16])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@]1(C(C)C)CC[C@@H](N(C)C2CCOCC2)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[C@]1(C(=O)O)CC[C@@H](N(C)C2CCOCC2)C1
Reaction time: 48 h
Yield: 95.5 %

Procedure:
A solution of methyl (1S,3R)-1-isopropyl-3-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclopentanecarboxylate (1.0 g, 3.5 mmol) in 1:1 THF/MeOH (20 mL) was treated with a solution of LiOH.H2O (735 mg) in 10 mL of water. After several hours very little hydrolysis was observed by HPLC-MS analysis so the reaction mixture was warmed to reflux and stirred for 2 days. The pH of the reaction mixture was then adjusted to 7 and the mixture was concentrated. The residue was suspended in 50% methanol/DCM, filtered, and the filtrate was concentrated to afford 900 mg of (1S,3R)-1-isopropyl-3-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclopentanecarboxylic acid which required no further purification.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:7](=[O:9])[C:4]3[CH:3]=[CH:2][C:1]([CH3:10])=[CH:6][CH:5]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(C)cc3)nc12

Procedure:
From para-toluic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+35.1° (c=0.84, CHCl3), ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH:5]=[CH:4]1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN(C=O)C.[NH4+].[Cl-]>[CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]2[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18])=[O:13]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: N#Cc1ccccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
NaH (60% in mineral oil, 303 mg, 7.58 mmol, Eq: 1.1) was added to a solution of 1H-indole-4-carbaldehyde (1 g, 6.89 mmol, Eq: 1.00) in DMF (12 mL) at 0° C. After 10 min., the mixture was warmed to RT and treated with sonication for 2 min. 2-Fluorobenzonitrile (918 mg, 822 μl, 7.58 mmol, Eq: 1.1) was added and the mixture was treated with sonication for 3 min. After 3 h the mixture was diluted with sat. NH4Cl, extracted with EtOAc, the combined extracts washed with H2O and concentrated. The residue was tritrurated with Hexane/Et2O to give 2-(4-formyl-1H-indol-1-yl)benzonitrile (1.2 g, 70.7%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][NH2:19].[OH:20][CH:21]([CH2:24]O)[CH:22]=[O:23]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][N:19]=[CH:24][CH:21]([OH:20])[CH2:22][OH:23]
Reactant: O=CC(O)CO
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CON)c1Cl
Product: Cc1ccc(Cl)c(Nc2ccccc2CON=CC(O)CO)c1Cl

Procedure:
The title compound is prepared by the reaction of O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl]hydroxylamine, prepared as in Example 1, steps 1-3, with 2,3-dihydroxypropionaldehyde.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[NH4+].[Cl-]>O1CCCC1.CCOCC>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
In 75 ml of dry tetrahydrofuran was dissolved 3.81 g of 9-benzylamino-3,4-dihydroacridin-1(2H)-one with mechanical stirring. The solution was cooled in ice under N2 and 5.9 ml (0.5 eq) of 1.1M LiAl4 solution in ether was added dropwise. After 0.5 hour the reaction was complete based on thin layer chromatography analysis. The excess hydride was neutralized with 0.5 ml of saturated NH4Cl solution and the inorganic salts were extracted into 30% potassium hydroxide. The tetrahydrofuran solution was decanted and evaporated to a solid which was recrystallized from 1:10 dichloromethane/EtOAc to yield 2.89 g (75%) of a solid, melting point 159° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:15])=[C:8]([CH:16]([CH3:18])[CH3:17])[CH:7]=1.C1COCC1.O>CCCCCCC.C(OCC)(=O)C>[OH:15][C:9]1[C:8]([CH:16]([CH3:18])[CH3:17])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:11][C:10]=1[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)CCc1cc(C(C)C)c(O)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: CC(C)c1cc(CCC(=O)O)cc(C(C)C)c1O
Yield: 67 %

Procedure:
A solution of 2.64 g (10 mmol) of 3-(4-hydroxy-3,5-diisopropylphenyl)propanoic acid methyl ester (cf. U.S. Pat. No. 3,642,868) and 0.84 g (20 mmol) of LiOH,H2O in 80 ml of a 1/1 mixture THF/H2O was stirred at 20° C. for 7 hours. After evaporation of THF under reduced pressure, the aqueous solution was acidified with KHSO4 (1M) and extracted twice with 50 ml EtOAc. The organic layer was decanted, washed with 20 ml brine, dried over MgSO4 and filtered. The residue of evaporation was triturated with heptane to yield a white powder (67%). Melting, point: 106-106.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[S:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][C:3]1[S:4][C:5]2[S:6][CH:7]=[CH:8][C:9]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2sccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Br)sc2sccc12
Yield: 36.7 %

Procedure:
3-Methylthieno[2,3-b]thiophene (Step 1, 450 mg, 2.92 mmol) was dissolved in carbon tetrachloride (7 mL) under nitrogen. N-Bromosuccinimide (0.52 g, 2.92 mmol) and benzoyl peroxide (75% in water; 0.10 g, 0.29 mmol) were added and the reaction heated to reflux for 6 hours. The solvent was removed in vacuo and the residue taken up in dichloromethane then filtered onto a column of silica and eluted with isohexane to give 2-bromo-3-methylthieno[2,3-b]thiophene (0.25 g, 37%). 1H NMR (500 MHz, CDCl3) δ 7.38 (1H, d, J=5.2 Hz), 7.13 (1H, d, J=5.2 Hz), 2.34 (3H, s).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCCCCCCCCCCC>C(O)(C)C>[CH:7]1[CH:6]=[CH:5][C:4](/[CH:3]=[CH:2]/[CH2:1][OH:10])=[CH:9][CH:8]=1
Reactant: O=CC=Cc1ccccc1
Solvent: CC(C)O
Solvent: CCCCCCCCCCCC
Product: OC/C=C/c1ccccc1

Procedure:
In a three-necked flask provided with reflux condenser and magnetic stirrer, 0.5 g (3.8 mmol) of cinnamaldehyde (trans-3-phenyl-2-propanol) and 12 g of isopropyl alcohol (for a starting material/catalyst ratio=1:1) or 1.5 g (11.3 mmol) of cinnamaldehyde and 36 g of isopropyl alcohol (starting material/catalyst=3:1) were refluxed under argon with 0.5 g of catalyst and 1.5 g of dodecane (as GC standard). After the end of the reaction time, the reaction mixture was analyzed by gas chromatography and the yield was determined. The results are summarized in Table 2 below:
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[CH:27]12[CH2:36][CH:30]([CH2:31][CH:32]1[C:33]([OH:35])=[O:34])[CH:29]=[CH:28]2>[Cl-].C[N+](C)(C)C>[CH:27]12[CH2:36][CH:30]([CH2:31][CH:32]1[C:33]([O:35][CH2:9][CH:8]([OH:10])[CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:34])[CH:29]=[CH:28]2
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: C=C(C)C(=O)OCC1CO1
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COC(=O)C1CC2C=CC1C2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Glycidyl methacrylate (43 g), containing 0.13 g of 2,6-di-tert. butyl-p-cresol and 0.26 g of tetramethylammonium chloride, was heated to 100° C. and bicyclo[2.2.1]hept-2-ene-6-carboxylic acid (41.8 g) was added slowly over about 1 hour, so that the temperature of the mixture did not exceed 105° C. Heating at 100° C. was continued for a further three hours, by which time the epoxide content of the product was negligible. The above-mentioned ester was a colourless mobile liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl.CO>[C:16]([CH2:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]2[CH:5]=[CH:4][N+:3]([O-:27])=[C:2]([CH3:1])[CH:7]=2)=[N:9][CH:10]=1)([OH:18])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(-c2ncc(CC(=O)O)cc2C)ccn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(CC(=O)O)cnc1-c1cc[n+]([O-])c(C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetic acid 156-5 (100 mg, 0.41 mmol) in dichloromethane (3 mL) and methanol (0.5 mL) was added mCPBA (91 mg, 0.41 mmol) in small portions at 0° C. The mixture was stirred for 3 hours at 0° C., and then was concentrated to dryness to give 4-(5-(carboxymethyl)-3-methylpyridin-2-yl)-2-methylpyridine 1-oxide 156-6 as white solid, which was used for next step without further purification. MS m/z 259.1 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[N:12](COCC[Si](C)(C)C)[CH:11]=1.B(Br)(Br)Br.N>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: COc1ccc(C)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccc(O)c(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 72 %

Procedure:
(S)-2-(1-((5-(2-Methoxy-5-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (45 mg, 0.07 mmol) was treated with boron tribromide (1M in dichloromethane, 1.6 mL, 1.6 mmol) and a solution of ammonia (7N in methanol, 1.6 mL, 11.2 mmol) according to the method described in Example 41 to give 23.6 mg (72% yield) of the title. Purity 97%.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=2)[N:18]=1.[K][S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][K]>>[Cl:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][C:26]1=[N:25]2
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: N#CC(C#N)=C(S[K])S[K]
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: N#CC(C#N)=C1Sc2nc3ccc(Cl)cc3nc2S1
Yield: 78 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 3.0 g of 2,3,6-trichloroquinoxaline and 3.5 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark brown powder weighing 3.0 g with a calculated yield of 78 percent and has a melting point greater than 300° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[C:14]([CH3:19])=[N:15][O:16][C:17]=3[CH3:18])[C:10]=2[N:11]=1.[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[C:14]([CH3:19])=[N:15][O:16][C:17]=4[CH3:18])[C:10]=3[N:11]=2)=[CH:23][N:22]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Cc1noc(C)c1Nc1ncnc2ccc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1Nc1ncnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4F)c3)nc12
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine (Intermediate 21) (0.040 g, 0.145 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.069 g, 0.160 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 μmol) and 1 N aq. sodium bicarbonate (0.290 ml, 0.290 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(3,5-dimethylisoxazol-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.021 g, 27%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.30 (3H, s), 2.45 (3H, s), 6.89-7.05 (2H, m), 7.27 (1H, s), 7.79-7.92 (1H, m), 8.20 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.36 (1H, d, J=8.8 Hz), 8.73 (1H, s), 8.76 (1H, s), 8.89 (1H, s). m/z=544.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.S(OC)(O[CH3:14])(=O)=O>C(O)(=O)C>[CH3:14][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CC(=O)O
Product: Cc1ncc([N+](=O)[O-])n1C
Yield: 75.5 %

Procedure:
127 parts of 2-methyl-5-nitroimidazole, 350 parts of acetic acid and 126 parts of dimethyl sulfate are boiled under reflux for 4 hours. The acetic acid is distilled off in vacuo and the residue is dissolved in 500 parts of water and adjusted to pH 1.8 with aqueous ammonia solution. After cooling to from 0° to 5° C. the unreacted 2-methyl-5-nitroimidazole is suction filtered, the filtrate is adjusted to pH 10 and after cooling the 1,2-dimethyl-5-nitroimidazole is isolated. In addition to 30.4 parts of starting material (II) there is obtained 81 parts of 1,2-dimethyl-5-nitroimidazole (melting point 140° C.); this is equivalent to a yield of 75.5% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:16](O)=O.C=O.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
4-Fluorophenyl piperidin-4-yl methanone 1.79 g (8.66 mmol) was added to formic acid (1.5 ml) and formaldehyde 1.05 ml and the reaction mixture was stirred at 55-60° C. for 3 hours. After cooled down, water was added, basified with potassium hydroxide pellets to pH>10 and extracted with ethyl ether 3×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1.88 g of desired product in 98% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[C:17]([CH2:18][N:19]([CH2:33][C:34]2[CH:51]=[CH:50][C:37]3[N:38]([CH2:48][CH3:49])[C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:36]=3[CH:35]=2)[CH2:20][CH2:21][N:22]2[CH:27]=[CH:26][C:25]3[O:28][C:29]([CH3:31])=[CH:30][C:24]=3[C:23]2=[O:32])=[CH:16][CH:15]=[CH:14][N:13]=1)(=O)C>CO>[CH2:48]([N:38]1[C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:36]2[CH:35]=[C:34]([CH2:33][N:19]([CH2:18][C:17]3[C:12]([CH2:11][OH:10])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:20][CH2:21][N:22]3[CH:27]=[CH:26][C:25]4[O:28][C:29]([CH3:31])=[CH:30][C:24]=4[C:23]3=[O:32])[CH:51]=[CH:50][C:37]1=2)[CH3:49]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3COC(C)=O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Potassium carbonate (2.0 g) was added to a methanol solution (30 mL) of (3-((((1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl) (2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)pyridin-2-yl)methyl acetate (3.0 g) and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and evaporated. The residue was purified by column-chromatography (methanol:ethyl acetate=0:100→1:9) to give the titled compound as ivory powder (1.95 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:19]1([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of [(S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tertbutyl ester (1.77 g) in DCM (4 mL) was added TFA (20 mL) and the resulting mixture was stirred at RT for 15 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM and then the combined organic layers were dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) affording (S)-1-(3-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine as colourless gum (540 mg, 20% over three steps). LCMS: RT 1.65 min [M−NH2]+ 222.0.