Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[S:4][N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+].CC#N>O>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: CC(C)COC(=O)NC1CCN(c2nc(Br)ns2)CC1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)NC1CCN(c2nc(-c3ccccc3O)ns2)CC1
Temperature: 175 °C

Procedure:
A mixture of isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate (0.38 g, 1.1 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (0.35 g, 1.6 mmol), Pd(Ph3)4 (12 mg, 11 μmol), K2CO3 (0.29 g, 2.1 mmol), CH3CN (3.0 mL), and H2O (0.3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 175° C. for 15 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 377.3 (M+H)+ at 3.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]CC)=[O:9].[OH-].[K+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccccn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To an EtOH solution (40 mL) of ethyl 2-pyridylacetate (5.00 g, 30.27 mmol, 1 equiv) was added an aqueous solution (13 mL) of KOH (2.04 g, 36.32 mmol, 1.2 equiv). The resulting solution was stirred at 50° C. (2 h). The solution was concentrated to one third of the original volume and then washed with Et2O (3×20 mL). The aqueous layer was neutralized with aqueous concentrated HCl (3.0 mL), and then concentrated in vacuo. The crude 2-(pyridin-2-yl)acetic acid (4.15 g) was used without further purification for the next step: Rf=0.06 (EtOAc); 1H NMR (DMSO-d6) δ 3.93 (s, CH2), 7.54 (dd, J=1.8, 5.4 Hz, H4), 7.60 (d, J=7.9 Hz, H6), 8.06 (dt, J=1.8, 7.9 Hz, H5), 8.64 (d, J=5.4 Hz, H3).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][C:9](=O)[C:8]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:29])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:29][C:9]1[C:8]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:19])([F:18])[F:20])[CH:15]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nnn[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
4-Phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-1H-quinolin-2-one (160 mg, 448 μmol) was twice co-evaporated with toluene (5 ml). Then toluene (5 ml), phosphorus oxychloride (446 mg, 271 μl, 2.91 mmol) and N,N-diisopropylethylamine (72.3 mg, 97.8 μl, 560 μmol) were added and the mixture was heated to 70° C. for 5 h. Then all volatiles were removed and toluene (5 ml) was added and evaporated twice. Then ethanol (5 ml) was added and evaporated. Water and methanol were added to the remaining residue and the solid was filtered off and dried to obtain the title compound (107 mg, 64%) as brown solid. MS (ESI): 374.3 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].CC(C)(O)C#N.[Cl:16][CH2:17]CCO>O.[Cl-].[Zn+2].[Cl-].[Zn]>[Cl:16][CH2:17][CH2:2][CH2:3][O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7]
Reactant: OCCCCl
Reactant: CC(C)(C#N)OCCCl
Agent: CC(C)(O)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C#N)OCCCCl
Temperature: 60 °C
Reaction time: 30 h

Procedure:
Zinc chloride (68.1 g, 0.5 mol) was fused using the procedure described for the synthesis of intermediate 23, 2-(2-chloroethoxy)-2-methylpropanenitrile. The molten zinc was cooled and the flask flushed with nitrogen. The flask was loaded with acetone cyanohydrin (46 mL, 0.5 mol) and 3-chloropropanol (64 mL, 0.75 mmol) and the reaction mixture stirred at 60° C. for 30 hours. The mixture was then diluted with water (200 mL) and extracted with dichloromethane (1×200 mL and 3×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in-vacuo. The crude product was purified by vacuum distillation (bp 78-84° C., 10 mmHg) to give the title compound (41 g) as a 2:1 mixture with residual 3-chloropropanol. 1H NMR (500 MHz, CDCl3) δ ppm: 3.72 (2H, t, J=5.8 Hz), 3.63 (2H, t, J=6.4 Hz), 2.04 (2H, m), 1.57 (6H, br s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[F:9])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 60 °C
Yield: 77 %

Procedure:
A mixture of 3.1 parts of 3,6-dichloropyridazine, 3 parts of 1-(2-fluorophenyl)piperazine. 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 72 parts of N,N-dimethylformamide was stirred and heated over weekend at 60° C. The reaction mixture was poured into water. The precipitated product Was filtered off and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 4.5 parts (77%) of 3-chloro-6-[4-(2-fluorophenyl)-1-piperazinyl]pyridazine; mp. 148.0° C. (compound 9).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].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>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20](=[O:22])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=3)=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ccn1
Yield: 31.8 %

Procedure:
A solution of 3-[4-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)phenyl]-propanoic acid (270 mg, 0.90 mmol), 3-(trifluoromethyl)aniline (158 mg, 0.98 mmol), HATU (409 mg, 1.07 mmol), and DIPEA (348 mg, 2.69 mmol) in DMF (5 mL) was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with 1N HCl and brine. The organic solution was dried over MgSO4, filtered, and concentrated to give A-4 as a white solid (127 mg, 32%). 1H NMR (300 MHz, d6-DMSO) δ: 10.28 (s, 1H), 8.76 (m, 1H), 8.47 (d, 1H), 8.08 (br s, 1H), 7.75 (br d, 1H), 7.53 (t, 1H), 7.31-7.42 (m, 4H), 7.08-7.19 (m, 3H), 2.97 (t, 2H), 2.76 (d, 3H), and 2.71 (d, 2H). LCMS, FA: Rt=1.89 min, [MH+ 444.1].
Reaction SMILES: [CH3:1][C:2]1[N:3](CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[C:4]2[N:5]([N:7]=[CH:8][CH:9]=2)[N:6]=1.[CH3:47][C:48]1[N:49]=[C:50]2[CH:55]=[CH:54][N:53]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=4[C:69]4[N:73]([C:74]([C:87]5[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=5)([C:81]5[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=5)[C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[N:72]=[N:71][N:70]=4)=[CH:59][CH:58]=3)[N:51]2[N:52]=1>>[CH3:47][C:48]1[N:49]=[C:50]2[CH:55]=[CH:54][N:53]([CH2:56][C:57]3[CH:58]=[CH:59][C:60]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=4[C:69]4[N:73]([C:74]([C:81]5[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=5)([C:87]5[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=5)[C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[N:72]=[N:71][N:70]=4)=[CH:61][CH:62]=3)[N:51]2[N:52]=1.[CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:7]=[CH:8][CH:9]=2)[N:6]=1
Reactant: Cc1nn2nccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1nc2ccn(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Product: Cc1nn2nccc2[nH]1

Procedure:
In the same manner as described in Example 66, 2.61 g of 2-methyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 72a) and 1.15 g of 2-methyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 72b) were obtained from 1.11 g of 2-methyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:24])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[CH2:10][C:9]3=[CH2:23].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:24])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH:14]=[C:15]1[CH3:21])[CH2:10][C:9]3=[CH2:23]
Reactant: C=C1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C=C1CC2=CC(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Yield: 69.9 %

Procedure:
The organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is purified by column chromatography on silica gel thus giving pure 16α-fluoro-1β-methyl-7-methylenandrost-4-ene-3,17-dione (198 mg). 16α-fluoro-1β-methyl-7-methylenandrost-4-ene-3,17-dione (331 mg) and dichlorodicyanobenzoquinone (363 mg) are refluxed in dioxane solution (20 ml) for about 15 hrs. Then the precipitate is filtered off and the filtrate evaporated in vacuo. The residue is taken up in ethyl acetate and the organic solution washed, dried and evaporated in vacuo. The residue is chromatographed on silica gel using hexane/ethyl acetate as eluant to give pure 16α-fluoro-1-methyl-7-methylenandrosta-1,4-diene-3,17-dione (230 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH:5]([N:7]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[PH:8]([CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[CH2:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])=[O:9])[CH3:6])[CH3:2].N1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:42])[CH:5]([N:7]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[PH:8]([CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[CH2:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])=[O:9])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N(Oc1ccccc1)[PH](=O)CC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)N(Oc1ccccc1)[PH](=O)CC(C)=CCc1c(O)c2c(c(C)c1CC)COC2=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionic acid ethyl ester (7.5 mg, 0.012 mmol) was dissolved in TFA/DCM (10%, 0.3 mL) at −20° C. The reaction mixture was warmed to 0° C. and stirred at this temperature for 45 minutes. Pyridine (0.09 mL) was added the solvents were removed in vacuo. The crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized, yielding a white powder (5.5 mg, 87%). 1H NMR (300 MHz, CDCl3): δ=1.12-1.29 (m, 6H), 2.03 (s, 3H), 2.17 (s, 3H), 2.65-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m, 3H), 5.22 (s, 2H), 5.36 (m, 1H), 7.11-7.16 (m, 3H), 7.24-7.30 (m, 2H), 7.72 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.11, 27.57 ppm; MS=515 [M++1].
Reaction SMILES: S(Cl)(Cl)(=O)=O.[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11]O.[CH2:13]([N:15](CC)[CH2:16]C)C>C(Cl)Cl>[CH3:13][N:15]([CH2:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][NH:6]1)[CH3:16]
Reactant: CCN(CC)CC
Reactant: OC[C@@H]1CCCN1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CN(C)C[C@@H]1CCCN1
Temperature: -78 °C
Reaction time: 20 h

Procedure:
While cooling at −78° C., a solution of sulfuryl chloride (0.409 mL) in methylene chloride (30 mL) was added dropwise to a solution of (2S)-2-pyrrolidinemethanol (0.498 mL) and triethylamine (1.39 mL) in methylene chloride (30 mL) over a period of 10 minutes. The temperature of the resultant mixture was gradually returned to room temperature, followed by stirring of the mixture for 20 hours. The reaction mixture was partitioned between 1N aqueous hydrochloric acid and methylene chloride, and the organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and a solution of 2.0M dimethylamine in tetrahydrofuran (25 mL) was added to the residue, followed by stirring in a sealed tube at an external temperature of. 100° C. for 14 hours and 30 minutes, and then cooled in air. Trifluoroacetic acid (one droplet) was added thereto. The resultant mixture was further stirred in a sealed tube at an external temperature of 100° C. for 21 hours and then cooled in air. The solvent was removed at normal pressure, and 2N aqueous sodium hydroxide (50 mL) was added to the residue, followed by stirring at 100° C. for 15 hours. The resultant mixture was cooled in air. Diethyl ether was added thereto for partitioning the mixture, and the organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed at normal pressure, to thereby give (2S)-2-dimethylaminomethylpyrrolidine.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CCOCCO>[C:16]([NH:24][N:25]=[C:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1c(O)nc2ccccc2c1O
Reactant: NNC(=O)c1ccncc1
Solvent: CCOCCO
Product: CC(=NNC(=O)c1ccncc1)c1c(O)nc2ccccc2c1O
Yield: 84.5 %

Procedure:
20.3 g of 3-acetyl-2,4-dihydroxyquinoline and 13.8 g of isonicotinic acid hydrazide are condensed in 180 ml of ethyl cellosolve analogously to Example 1, yielding 27.2 g of 3-acetyl-2,4-dihydroxyquinoline isonicotinoylhydrazone. 3.2 g of this product are suspended in 25 ml of dimethylformamide and treated with a solution of 2.7 g of nickel(II) acetate·4H2O in dimethylformamide. The resulting mixture is stirred for 2 hours at 80°-90° C. and the product is then isolated by filtration and subsequently washed with isopropanol and then with water. After the product has been dried under vacuum at 70°-80° C., 3.5 g of a yellow powder of the following formula: ##STR23## as the 1:1 nickel complex, are obtained which gives the following microanalysis:
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)[CH2:14][CH2:13][C:12]1=O.C(OC(C)=C)(=O)C.C(N(CC)CC)C.C(=O)C1C=CC=CC=1>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[C:2]1([C:1]2[CH:12]=[C:13]([CH3:14])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Agent: C=C(C)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=Cc1ccccc1
Product: Cc1cc(-c2ccccc2)no1
Temperature: 4 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Benzaldehyde oxime (20.0 g, 0.165 mole) is dissolved in DMF (250 mL) and cooled to 4° C. in an ice bath. N-chlorosuccinimide (33.1 g, 0.248 mole) is added to the reaction mixture, and the mixture is stirred for one hour. Isopropenyl acetate (41.3 g, 0.41 mole) and triethyl amine (24.8 g, 0.247 mole) are added via an equal-pressure addition funnel to the solution of benzaldehyde hydroxamic chloride. The ice bath is removed and the mixture is stirred for 24 hours. The mixture is then taken up into ethyl acetate (1 L) and washed with water (2×1 L). The organic layer is dried over sodium sulfate and evaporated to give a residue. Flash chromatography (hexane/ethyl acetate 9:1) affords 12.0 g of 3-phenyl-5-methylisoxazole a a yellow oil.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(Cl)Cl.[C:24](Cl)([Cl:26])=[O:25]>C(Cl)Cl>[Cl:26][C:24]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:25]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 270 parts of n-octadecanol in 150 parts of chloroform is added during 90 mins to a stirred solution of 300 parts of phosgene in 450 parts of methylene dichloride at 0°-5° C. The reaction mixture is then stirred a further 2 hours at 0°-5° C., 2 hours at 10° C. and 12 hours at 25° C. Excess phosgene and hydrogen chloride are removed by passing a stream of dry nitrogen. The residue is evaporated to constant weight at 100° C. under reduced pressure to give 327 parts of n-octadecyl chloroformate as a pale yellow oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CS(O[CH2:27][C:28]([C@@H:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]1)([CH3:30])[CH3:29])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:30][C:28]([C@@H:31]4[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]4)([CH3:27])[CH3:29])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC[C@@H](C(C)(C)COS(C)(=O)=O)O1
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC1(C)OC[C@@H](C(C)(C)COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)O1
Temperature: 85 °C
Yield: 134.8 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.09 g, 0.34 mmol), (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl methanesulfonate (0.11 g, 0.45 mmol) and cesium carbonate (0.22 g, 0.69 mmol) were added to 1 to 2 mL of DMA and heated to 85° C. for 4-5 hours. The reaction was concentrated and treated with water and ethyl acetate. The reaction was extracted several times with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified on Silica gel using 2% NH4OH in isopropyl acetate and DCM to provide 200 mgs of the desired product (85% pure).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.[CH3:20][N:21]([C@@H:29]([CH3:45])[C:30](=[O:44])[NH:31][C@H:32]1[CH2:38][O:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34][C:33]1=[O:43])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[Cl:46][C:47]1[N:48]([C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[C:60]#[N:61])[C:49]2[C:54]([C:55]=1[CH2:56]O)=[CH:53][CH:52]=[CH:51][CH:50]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CO>[Cl:46][C:47]1[N:48]([C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[C:60]#[N:61])[C:49]2[C:54]([C:55]=1[CH2:56][N:34]1[C:33](=[O:43])[C@@H:32]([NH:31][C:30](=[O:44])[C@@H:29]([N:21]([CH3:20])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH3:45])[CH2:38][O:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]1=3)=[CH:53][CH:52]=[CH:51][CH:50]=2
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1-n1c(Cl)c(CO)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(Cl)n(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
Diethyl azodicarboxylate solution 40 wt. % in toluene (DEAD 40% w/w, 360 mg, 377 μl, 828 μmol, Eq: 2) was added to a solution of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (226 mg, 621 μmol, Eq: 1.5), 2-(2-chloro-3-(hydroxymethyl)-1H-indol-1-yl)benzonitrile (117 mg, 414 1=01, Eq: 1.00) and Ph3P (217 mg, 828 μmol, Eq: 2) in THF (5 mL) and the mixture was stirred at RT for 2.5 d. The mixture was diluted with MeOH (10 mL), concentrated and the residue purified by preparative TLC to give tert-butyl (S)-1-((S)-5-((2-chloro-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (130 mg, 50%) as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[NH:23][N:22]=2)=[N:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:30](I)[CH3:31].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[N:23]([CH2:30][CH3:31])[N:22]=2)=[N:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)nc2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(OCc3ccccc3)cn2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of K2CO3 (212 mg, 1.53 mmol), 3-[5-(benzyloxy)pyridin-2-yl]-1H-pyrazolo[4,3-b]pyridine (232 mg) in DMF (3 mL) was added EtI (0.064 mL), and stirred at room temperature overnight. The mixture was added to saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was separated, washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (224 mg).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][NH:7][NH2:8].C(N(CC)CC)C.Cl[C:17](=[N:25][N:26]=[C:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[NH:8][N:7]([CH3:6])[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:26][N:25]=1
Reactant: CNN
Reactant: ClC(=NN=C(Cl)c1ccccc1Cl)c1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1NC(c2ccccc2Cl)=NN=C1c1ccccc1Cl

Procedure:
The suspension containing 3.74 g (0.026 mol) of methylhydrazine sulfate, 11.9 ml (0.086 mol) of triethylamine in 11.2 ml of abs. ethanol is boiled under reflux while portionwise adding 1.12 g (0.0032 mol) of bis(alpha,2-dichlorobenzylidene)hydrazine.