Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:52].Cl.[NH2:54][C@@H:55]([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:56]([OH:70])[CH2:57][NH:58][C:59]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[CH:69])[CH:63]=2)[CH2:61][CH2:60]1>O1CCCC1.CO.O.O.[OH-].[Li+].C(OCC)(=O)C>[ClH:52].[ClH:52].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([NH:54][C@@H:55]([CH2:71][C:72]1[CH:73]=[C:74]([F:79])[CH:75]=[C:76]([F:78])[CH:77]=1)[C@H:56]([OH:70])[CH2:57][NH:58][C:59]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[CH:69])[CH:63]=2)[CH2:61][CH2:60]1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: CCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3cc(C)cc(CN(C)CCCC)c3)CC2)c1
Reaction time: 16 h

Procedure:
Methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (122 mg, 0.49 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (41 mg, 1 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (350 μL, 2 mmol), HATU (240 mg, 0.63 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride prepared by the method in Example SP-272 (215 mg, 0.5 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 574.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[K+].Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1.C(O)(=O)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:18][O:17][C:15](=[O:16])[CH:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:33][CH:34]=2)=[CH:23][CH:24]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCCOc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A mixture of 1.55 g of p-chlorophenol, 0.47 g of 60% sodium hydride-oil dispersion and 20 ml of tetrahydrofuran is stirred at room temperature for 90 minutes. To the mixture is added 2.22 g of potassium iodide, 1 ml of hexamethylphosphoramide and dropwise 5.04 g of methyl bromo{p-[2-(p-tert.-butylphenoxy)ethoxy]phenyl}acetate in 30 ml of tetrahydrofuran. The mixture is refluxed for 18 hours and poured into 350 ml of ice-water containing 1 ml of acetic acid. After stirring in an ice bath for 30 minutes, the mixture is filtered and the solid washed with water to give 5.5 g of product as tan crystals. Recrystallization by dissolving in acetone, adding hexane and distilling off the acetone gives 3.9 g of white crystals, mp 128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:41]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:40])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:39])[C:20]=2[N:21]2[CH2:27][CH2:26][CH:25]([O:28]CC3C=CC(OC)=CC=3)[CH:24]([OH:38])[CH2:23][CH2:22]2)[N:13]=1.[H][H].C(O)(C(F)(F)F)=O>CO.C(Cl)Cl.[Pd]>[NH2:41][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:39])[C:20]=1[N:21]1[CH2:22][CH2:23][C@@H:24]([OH:38])[C@H:25]([OH:28])[CH2:26][CH2:27]1)=[O:40]
Reactant: [H][H]
Reactant: COc1ccc(COC2CCN(c3c(NC(=O)c4nc(-c5c(F)cccc5F)sc4NC(=O)OC(C)(C)C)cnn3C)CCC2O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](O)[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of tert-butyl N-(2-(2,6-difluorophenyl)-4-((5-(4-hydroxy-5-((4-methoxyphenyl)methoxy)azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate (0.50 g, 0.73 mmol) in MeOH (25 mL) was added 10% Pd/C (0.20 g). The mixture was stirred under a 50 psi atmosphere of hydrogen at room temperature for 18 hr. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to give a colourless solid. The crude solid was dissolved in DCM (10 mL) and TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hr, concentrated under reduced pressure and the crude residue was dissolved in a 1/1 mixture of MeOH/2 M aqueous NaOH (40 mL) and heated at 50° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with DCM (50 mL) and EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via preparative HPLC gave 490 as a pale yellow solid (86 mg, 25% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.72-8.63 (m, 1H), 7.61-7.45 (m, 4H), 7.31-7.23 (m, 2H), 4.57 (s, 2H), 3.63 (s, 3H), 3.52 (d, J=6.5 Hz, 2H), 3.20-3.05 (m, 4H), 1.94-1.86 (m, 2H), 1.74-1.64 (m, 2H). LCMS (ES+) m/z 465 (M+1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]3[C@H:18]4[C@H:28]([CH2:29][CH2:30][C@:13]23[CH3:14])[C@:26]2([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]2)[CH2:20][CH2:19]4)=[O:11])[CH2:3][CH2:2]1.C(O)(C)C.C(N(CC)CC)C>O>[OH:31][C@@H:23]1[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[C:10]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:11])[CH2:22]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)OCCN3CCOCC3)CC[C@@H]12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)OCCN3CCOCC3)CC[C@@H]12
Yield: 72.3 %

Procedure:
A solution of 17β(2'-morpholinoethoxycarbonyl)-5α-androstan-3-one (750 mg.) in the minimum volume of isopropanol was added to a stock solution (35 ml.) of chloroiridic acid/trimethyl phosphite complex preneutralised to pH5 with triethylamine (3 ml.). This solution, after being refluxed for 4.5 hours, was poured into water and extracted with chloroform. The chloroform solution was washed with water, dried (MgSO4) and filtered through a short column of florisil before evaporation to a gum (740 mg.). Purification by preparative t.l.c. (ethanol/chloroform 1:19) afforded title compound (545 mg.) as a white froth; [α]D + 37.8, (c 0.9%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([CH2:20][O:21]C(=O)C)[O:8][C@@:6]1([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=2)[CH:26]=1)[OH:7])(=O)C.[F:41][C:42]([Si](C)(C)C)([F:47])[C:43]([F:46])([F:45])[F:44].[F-].[K+].C([O-])(O)=O.[Na+]>[Cu]I.CN(C=O)C>[OH:7][C@:6]1([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:42]([F:47])([F:41])[C:43]([F:46])([F:45])[F:44])=[CH:36][CH:35]=3)[CH:26]=2)[O:8][C@H:9]([CH2:20][OH:21])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(Cc3ccc(I)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [F-]
Solvent: CN(C)C=O
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A flask charged with 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-iodo-benzyl)-benzonitrile (0.16 g), pentafluoroethyltrimethylsilane (0.14 g), KF (43 mg), CuI (0.16 g), DMF (2 mL) and Ar atmosphere is heated at 60° C. for 24 h. Then, aqueous NaHCO3 solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is dissolved in methanol (8 mL) and treated with 4 M KOH solution (0.8 mL). The solution is stirred at room temperature for 1 h and then diluted with aqueous NaHCO3 solution. After removal of the methanol under reduced pressure, the residue is extracted with ethyl acetate, the combined organic extracts are dried and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CSC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16](=[O:27])[N:17]([C:19]2[CH:24]=[N:23][C:22]([CH2:25]O)=[CH:21][N:20]=2)[CH:18]=1.O>C(Cl)Cl>[Br:8][CH2:25][C:22]1[N:23]=[CH:24][C:19]([N:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]2=[O:27])=[N:20][CH:21]=1
Reactant: O=c1ccc(Cl)cn1-c1cnc(CO)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: O=c1ccc(Cl)cn1-c1cnc(CBr)cn1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a slurry of NBS (0.598 g, 3.36 mmol) in CH2Cl2 (10 ml)at 0° C. was added methylsulfide (0.296 ml, 4.035 mmol). The slurry was cooled to -20° C. and the alcohol from step 3 (0.532 g, 2.24 mmol) was added followed by CH2Cl2 (10 ml). The reaction was stirred at 0° C. for 3 hrs and then at room temperature for 24 hrs. The reaction was poured into water and extracted into CH2Cl2 and the combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 30:70) to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH3:8][N:9]([CH2:52][CH:53]=O)[C:10](=[O:51])[C:11]1[CH:50]=[CH:49][CH:48]=[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][C:18]=2[C:29]2[CH:34]=[C:33]([C:35](=[O:47])[NH:36][C@@H:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:31][N:30]=2)=[O:15])[CH:12]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>C(O)C>[CH3:8][N:9]([CH2:52][CH2:53][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)[C:10](=[O:51])[C:11]1[CH:50]=[CH:49][CH:48]=[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:19][C:18]=2[C:29]2[CH:34]=[C:33]([C:35](=[O:47])[NH:36][C@@H:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:31][N:30]=2)=[O:15])[CH:12]=1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: O=C1CNCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(CCN1CCNC(=O)C1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using piperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (5 mL), piperazin-2-one (20 mg, 0.20 mmol, 1.20 equiv). This was followed by the addition of acetic acid (20 mg, 0.33 mmol, 2.20 equiv). The mixture was allowed to react with stirring for 1 h at room temperature. To this was added NaBH3CN (22 mg, 0.35 mmol, 2.20 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 7 with sodium bicarbonate (2 mol/L). The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 40% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 91.4 mg product was obtained. This resulted in 91.4 mg (54%) of (S)—N1-methyl-N1-(2-(3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LCMS (ES, m/z): 714 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.94 (m, 1H), 8.70 (m, 1H), 8.40 (s, 2H), 8.12 (m, 3H), 7.85 (m, 1H), 7.72 (m, 3H), 7.17 (m, 3H), 5.39 (s, 1H), 3.94 (m, 3H), 3.56 (m, 7H), 3.09 (m, 3H), 2.86 (m, 3H), 1.95 (m, 8H).
Reaction SMILES: O.[I-].[I:3]C1C=[C+]C2NC3C([Se]C=2C=1)=CC(I)=CC=3.[I-].[CH2:20]([N:23]([C:27]1[CH:28]=[CH:29][C:30]2[NH:31][C:32]3[C:37]([SeH+:38][C:39]=2[CH:40]=1)=[CH:36][C:35]([N:41]([CH2:45][CH2:46]C)[CH2:42][CH2:43]C)=[CH:34][CH:33]=3)[CH2:24][CH2:25]C)[CH2:21]C.C(N(CC)CC)C.C(NCC)C>CO>[I-:3].[CH2:24]([N:23]([C:27]1[CH:28]=[CH:29][C:30]2[NH:31][C:32]3[C:37]([SeH+:38][C:39]=2[CH:40]=1)=[CH:36][C:35]([N:41]([CH2:42][CH3:43])[CH2:45][CH3:46])=[CH:34][CH:33]=3)[CH2:20][CH3:21])[CH3:25]
Reactant: CCCN(CCC)c1ccc2c(c1)[SeH+]c1cc(N(CCC)CCC)ccc1N2
Reactant: IC1=CC2=C([C+]=C1)Nc1ccc(I)cc1[Se]2
Agent: [I-]
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CC)c1ccc2c(c1)[SeH+]c1cc(N(CC)CC)ccc1N2
Reaction time: 48 h
Yield: 22 %

Procedure:
To a solution of 3,7-diiodo-phenoselenazin-ylium iodide hydrate (prepared as above for Compound 2) (2.83 g) in methanol (300 cm3) was added triethylamine (1.0 cm3) followed by diethylamine (10 cm3). The reaction was stirred for 48 hours. The residue remaining after removal of the methanol was taken up in dichloromethane and washed with dilute hydriodic acid (5% w/w) followed by water. The organic phase was isolated and dried (MgSO4). Flash column chromatography over silica gel 60 Å was performed on the crude material using a mobile phase of 85/15 methanol/water containing 3% w/v ammonium acetate. After isolation of the desired fractions and removal of the methanol, the product was extracted from the aqueous phase using dichloromethane. Concentration of the dichloromethane in vacuo and addition of an excess of diethyl ether resulted in precipitation of the product. The product was collected by filtration, washed with diethyl ether and dried to give 3,7-bis-(N,N-diethylamino)-phenoselenazin-5-ylium iodide as a dark blue powder, in 22% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12]([O-])([OH:14])=[O:13].C(=O)=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[K+].[OH-].[Na+].O.N>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methylquinoline (108.3 ml, 0.80 mol) is added in drops to 65% nitric acid (61 ml, 0.88 mol) at an internal temperature of 0-10° C. (dry ice cooling) within 45 minutes. After 1 hour, the precipitated nitrate is suctioned off and introduced in portions at an internal temperature of 0-6° C. in concentrated sulfuric acid (240 ml). After 30 minutes, potassium nitrate (6 g, 60 mmol) is added thereto, and it is stirred for 16 hours at room temperature. The batch is slowly poured onto ice/water, and a pH of 1.5 is set with 40% NaOH (˜500 ml). The precipitate is suctioned off, the filtrate is made alkaline with 25% ammonia water (pH 10) and filtered. The filter residue is dissolved in hot methanol (500 ml). During cooling, the 8-nitro-isomer crystallizes out. The mother liquor is concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate, whereby 53 g of the 2-methyl-5-nitroquinoline accumulates.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:31][CH2:32][OH:33])[CH2:20][N:21]([CH3:30])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:31][CH:32]=[O:33])[CH2:20][N:21]([CH3:30])[C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
A solution of oxalyl chloride (878 mg) in dichloromethane (5 mL) was cooled to -78° C. and was treated dropwise with a solution of dimethyl sulfoxide (595 mg) in dichloromethane (2 mL). The resulting mixture was stirred at -78° C. for 15 minutes, and was treated dropwise with a solution of N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide (1.22 g) in dichloromethane (10 mL)/dimethyl sulfoxide (2 mL). The mixture was stirred at -78° C. for 1 hour, was treated with triethylamine (1.75 g), warmed to room temperature and stirred for 1 hour. The mixture was then poured into water and extracted with dichloromethane. The organic extract was washed (water, brine), dried, filtered through activated magnesium silicate [Florisil (trademark)] and evaporated to afford the aldehyde as a pale yellow oil (1.18 g); MS: m/z=350[(M+1), 35Cl2 ].
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1>C1COCC1>[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39]([C:2]3[CH:17]=[CH:16][C:5]4[N:6]([C:9]5[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=5)[N:7]=[N:8][C:4]=4[CH:3]=3)([OH:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OCC(Cn2cc(C(=O)C(F)(F)F)c3ccccc32)O1
Reactant: Fc1ccc(-n2nnc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(Cn2cc(C(O)(c3ccc4c(c3)nnn4-c3ccc(F)cc3)C(F)(F)F)c3ccccc32)O1
Reaction time: 0.02 h
Yield: 55.5 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-benzotriazole (145 mg, 0.5 mmol) in anhydrous THF (3 mL) was added n-butyllithium (0.22 mL of a 2.5 M solution in hexanes, 0.55 mmol). After 1 minute, a chilled (−78° C.) solution of 1-[1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1H-indol-3-yl]-2,2,2-trifluoroethanone (185 mg, 0.57 mmol) in 1 mL of THF was added. After 30 minutes, the mixture was quenched with brine solution (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and solvent evaporated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-60% ethyl acetate in hexanes and fractions corresponding to MS m/z 541 (MH+) peak were pooled and concentrated in vacuo to afford 150 mg of the title compound as a brownish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].S([CH2:37][N+:38]#[C-:39])(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]3[O:18][CH:39]=[N:38][CH:37]=3)=[CH:19][CH:20]=2)[O:4][N:3]=1
Reactant: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(CCCCCOc2ccc(-c3cnco3)cc2)on1
Yield: 47.5 %

Procedure:
A suspension of 10.00 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde, 10.0 g of potassium carbonate and 7.14 g of tosylmethyl isocyanide (4-CH3C6H4 --SO2CH2NC) in 90 ml of methanol was heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with methylene dichloride. The extract was washed with water, the product isolated and recrystallized from isopropyl acetate-hexane. Further purification by flash filtration through a silica gel pad, eluting with isopropyl acetate, and recrystallization from isopropyl acetate-hexane gave 5.43 g (48%) of 3-methyl-5-{5-[4-(5-oxazolyl)phenoxy]pentyl}isoxazole, yellow powder, m.p. 91°-93° C.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCCN=C1CCCCC2>C(O)(C)C>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:18][CH2:17][C:16]#[N:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CC#N
Reactant: O=CC(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: N#CCCC(C=O)(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
Diphenylacetaldehyde (25.6 g), acrylonitrile (12.5 ml), and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU:2.5 g) were stirred in isopropyl alcohol (250 ml) with warming at 70° C. for 6 hours. The reaction mixture was concentrated to dryness and the group was purified by silica gel column chromatography. The crude crystal crop obtained was washed with isopropyl ether to provide the title compound (19.8 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:23]=[CH:22][C:17]4[N:18]=[CH:19][N:20]([CH3:21])[C:16]=4[CH:15]=3)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O.[OH-].[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:23]=[CH:22][C:17]4[N:18]=[CH:19][N:20]([CH3:21])[C:16]=4[CH:15]=3)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1cnc2ccc(C(C)(O)c3cnc4ccc(Cl)nn34)cc21
Agent: II
Agent: O=C([O-])O
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(Cl)nn12
Reaction time: 0.17 h

Procedure:
In a microwave vial, (rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(3-methyl-3H-benzoimidazol-5-yl)-ethanol (Stage 185.3, 650 mg, 1.507 mmol) was dissolved in AcOH (15 mL) under Argon. Iodine (1.148 g, 4.52 mmol) and H3PO2 (1.233 mL of a 50% aqueous solution, 11.3 mmol) were added and the mixture was submitted to MW-irradiation at 150° C. for 10 min. The mixture was diluted with water. It was basified until pH 5 with NaOH 10 M and then saturated NaHCO3 sol. until pH 7-8. It was then extracted with EtOAc one time. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. It was then dried under vacuum overnight to afford the title compound as a foam (tR 2.12 min (conditions 8), MH+=312).