Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:14]([OH:16])=O)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]([C:14]([Cl:19])=[O:16])=[C:11]=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(C(C(=O)O)C(=O)O)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=C=O)C(=O)Cl)c(Cl)c1
Temperature: 95 °C

Procedure:
7.6 g of 2-chloro-4,6-dimethylphenylmalonic acid according to Example (XXXV-1) were suspended in 22 ml of toluene and treated dropwise with 19.5 ml of thionyl chloride. The mixture was heated at 95° C. for 9.5 h, cooled and freed from the volatile constituents by passing argon through. The residues of thionyl chloride and the solvent were distilled off at 45° C. in a high vacuum. 6.6 g of 2-chloro-4,6-dimethylphenylchlorocarbonylketene were obtained as an oil which was slightly contaminated with 2-chloro-4,6-dimethylphenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]2[C:14](=O)[O:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:11]2)=[CH:4][C:3]=1[CH2:23][O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].O.[NH3:31].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:11][C:10]([C:14]([NH2:31])=[O:13])=[N:9]2)=[CH:4][C:3]=1[CH2:23][O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CCOCc1cc(NN=C2N=C(c3ccccc3F)OC2=O)ccc1Cl
Reactant: N
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCOCc1cc(-n2nc(C(N)=O)nc2-c2ccccc2F)ccc1Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
In 10 ml of acetone, 1.294 g (3 mmol) of 4-[4-chloro-3-[(3-methylbutoxy)methyl]phenyl hydrazono]-2-(2-fluorophenyl)-2-oxazolin-5-one synthesized in the similar way to Synthesis Examples 1-3 was suspended, followed by the addition of 0.6 ml of concentrated ammonia water and 30-minute stirring at room temperature. The resulting solution was made acid by adding 0.6 ml of concentrated hydrochloric acid and further stirred at 50° C. for 30 minutes. Acetone was distilled off and the residue was extracted by adding benzene and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were distilled off to obtain a crude product, and this crude product was purified by subjecting it to silica gel chromatography using hexane/ethyl acetate (1/2, v/v) as developing solvent and recrystallized from ethyl acetate-hexane to obtain 1.062 g (82.3% yield) of 1-[4-chloro-3-[(3-methylbutoxy)methyl]phenyl]-5-(2-flurophenyl)-1H-1,2,4-triazole-3-carboxamide (m.p. 113°-115° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])N.[BrH:14].N([O-])=O.[Na+].NC(N)=O>>[Br:14][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: Br
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Product: FC(F)(F)Oc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 1.75 h
Yield: 29 %

Procedure:
To a 0° C. solution consisting of 3-chloro-4-trifluoromethoxy-aniline (2.12 g, 10.0 mmol) and HBr (48% aq, 50 mL) was added NaNO2 (2 M aq., 917.7 mg, 13.3 mmol) dropwise at a rate such that the reaction temperature remained below 5° C. After stirring for 1.75 h, urea (330 mg, 5.5 mmol) was added and the mixture stirred for 20 min. A solution consisting of Cu(I)Br (2.96 g, 20.6 mmol) and HBr (48% aq., 13.1 mL) was then added while keeping the reaction temperature in the range of 0-5° C. Upon complete addition, the reaction mixture was heated to 85° C. for 2.5 h. After cooling to rt, the reaction mixture was poured into ice water (150 mL) and extracted with hexanes (100 mL). The aqueous layer was washed with CH2Cl2 (100 mL) and the combined organic phases washed with satd. aq. NaHCO3 (150 mL×2), dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (806 mg, 29%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([I:10])[C:3]=1[NH2:4].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([I:10])[C:3]=1[N:4]=[C:12]=[O:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(F)c(N)c(I)c1
Solvent: C1COCCO1
Product: Cc1cc(F)c(N=C=O)c(I)c1

Procedure:
A mixture of 2-fluoro-6-iodo-4-methylaniline (D1) (370 mg, 1.5 mmol), triphosgene (150 mg, 0.05 mmol), and dioxan (3 ml) was heated at reflux for 1 h 15 min then cooled and evaporated to give the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:20][C:21]1[CH:22]=[N:23][C:24]([O:18][C:10]2[C:9]([F:19])=[C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)[CH:13]=[CH:12][C:11]=2[CH:14]2[CH2:15][CH2:16][CH2:17]2)=[N:25][CH:26]=1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccc(C3CCC3)c(Oc3ncc(Br)cn3)c2F)cn1
Temperature: 120 °C

Procedure:
To a microwave vial containing a stir-bar was added 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (100 mg, 0.386 mmol), 5-bromo-2-chloropyrimidine (74 mg, 0.39 mmol), cesium carbonate (188 mg, 0.580), and DMSO (2 mL). The vial was sealed and heated in the microwave for 30 minutes at 120° Celsius. The mixture was cooled to rt then passed through a syringe filter and the filtrate subjected to HPLC purification to give the title compound. 1H NMR (500 MHz, 2 mL) δ 8.69 (d, J=1.5, 2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.79-7.69 (m, 1H), 7.27 (d, J=8.3, 1H), 3.72-3.58 (m, 1H), 2.23-2.10 (m, 3H), 2.02-1.94 (m, 1H), 1.89-1.75 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:12][O-:13].[Na+].Cl>CO.[Cu]I>[CH3:12][O:13][C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: C[O-]
Reactant: Clc1ncc(Br)c2cc[nH]c12
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cnc(Cl)c2[nH]ccc12
Temperature: 115 °C

Procedure:
A mixture of 4-bromo-7-chloro-6-azaindole (1 g), CuI (0.65 g) and NaOMe (4 mL, 25% in methanol) in MeOH (16 mL) was heated at 110-120° C. for 16 hours in a sealed tube. After cooling to room temperature, the reaction mixture was neutralized with 1N HCl to pH 7. The aqueous solution was extracted with EtOAc (3×30 mL). Then the combined organic layer was dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford a residue, which was purified by using silica gel chromatography to give 0.3 g of 4-methoxy-7-chloro-6-azaindole, Precursor 2e. MS m/z: (M+H)+ calcd for C8H8ClN2O: 183.03; found 183.09. HPLC retention time: 1.02 minutes (column B).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of commercial 4′-bromo-2,2,2-trifluoroacetophenone (100 mg) in 1.9 mL of methanol was added sodium borohydride (15 mg). The mixture was stirred at room temperature overnight. Water was added, extracted with methyl t-butyl ether (3×20 mL) washed with water and brine. It was dried with magnesium sulfate and the solvent removed under reduced pressure to yield the title compound and it was used as such for the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](=[S:25])[NH2:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][CH:27](Cl)[C:28](=O)[CH3:29]>>[Cl:26][CH2:27][C:28]1[N:24]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[S:25][CH:29]=1
Reactant: CCc1ccc(C2CC(C(N)=S)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CC(=O)C(Cl)Cl
Product: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
860 mg (2.38 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carbothioamide (Example 140A) and 362 mg (2.85 mmol) of dichloroacetone were reacted according to the General Method 3. Yield: 498 mg (43% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: C#CN1CCOCC1
Solvent: CCN(CC)CC
Product: O=c1cc(N2CCOCC2)oc2ccc(Cl)cc12
Yield: 44.7 %

Procedure:
The methyl ester of 5-chlorosalicylic acid (2.00 g, 10.7 mmol) is mixed with ethynyl morpholine (neat, 1.00 g, 9.00 mmol) dropwise. The reaction is exothermic. When the mixture cools, triethylamine (TEA, 1 drop) is added and the liquid mixture immediately crystallized. The mixture is chromatographed (flash, SiO2, CH2Cl2 /EtOH, 95:5) to yield 6-chloro-2-(4-morpholinyl)-4H-1benzopyran-4-one (1.07 g, 45%). Mp 194°-5° C.; IR (mull) 2949, 2946, 2869, 2855, 1640, 1615, 1566, 1464, 1450, 1437, 1345, 1246, 1118, 822, 787 cm-1 ; 1H-NMR (CDCl3, 200 MHz, δ) 8.11 (d, J=2.5 Hz, 1H), 7.49 (dd, J=8.7, 2.5 Hz, 1 H), 7.23 (d, J=8.7 Hz, 1H), 5.49 (s, 1H), 3.85-3.82 (m, 4 H), 3.53-3.50 (m, 4 H); UV (EtOH) λ max (ε) 217 (31,360), 230 (24,900), 245 sh (12,100), 2908 h (11,170), 301 (15,810) , 315 (16,070); Mass Spectrum: ions at m/e (relative intensity) 267 (35), 265 (100), 210 (24) 209 (22), 208 (74), 207 (31), 180 (47), 154 (27), 126 (19), 52 (21); High resolution MS calc'd. for C13H12NO3Cl: 265.0506. Found: 265.0512. Anal. calc'd. for C13H14NO3Cl: C, 58.77; H, 4.55; N, 5.27; Cl, 13.34. Found: C, 58.52; H, 4.66; N, 5.11; Cl, 13.58.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(Cl)Cl.[CH2:21](O)[CH3:22]>CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:21][CH3:22])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4 g of the product of Step A, 3.4 g of dicyclohexylcarbodiiumide and 6 mg of 4-dimethylamino-pyridine were added to 30 ml of methylene chloride followed by the addition of 1.5 ml of ethanol and the mixture was stirred at 20° C. for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 4.25 g of tert.butyl (1R, cis)2,2-dimethyl-3-(ethoxycarbonyl-ethynyl)-cyclopropane-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][C:12](OCCCC)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCOc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCCCO)cc1
Temperature: -5 °C

Procedure:
This ester 21.0 g was dissolved in 500 ml dry ether and cooled to -5° C. in an ice/acetone bath. To the cold solution was added, cautiously, a slurry of 3.5 g lithium aluminum hydride in 100 ml dry ether. After one hour the excess lithium aluminum hydride was destroyed by the cautious addition of 200 ml ethyl acetate, then 50 ml water. The solution was filtered and the filtate partitioned between 200 ml ether - 200 ml water. The organic layer was removed, dried, and evaporated to a yellow oil which was vacuum distilled (116° C./0.35 mm) over potassium carbonate to a clear colorless oil, 3-p-t-butylphenoxypropanol, 10.1 g (64%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CC(O)C>[N:13]1([C:2]2[N:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Clc1nccc(-c2cccs2)n1
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: c1csc(-c2ccnc(N3CCNCC3)n2)c1
Temperature: 160 °C

Procedure:
To a microwave tube was added 2-chloro-4-thiophen-2-yl-pyrimidine (20 mg, 0.1 mmol), piperazine (26 mg, 0.3 mmol) and 2-propanol (0.6 mL). The resulting mixture was heated at 160° C. for 60 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:43])[C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([N:25]2[C:36](=[O:37])[C:35]4[C:34](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:33]2=[O:43])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N)nccc3c2)C1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N4C(=O)c5ccccc5C4=O)nccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of (S)-3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid tert-butyl ester (380 mg, 1.11 mmol) and triethylamine (1.5 ml, 11.1 mmol) in anhydrous tetraydrofuran (1.5 ml) was added phthaloyl dichloride (170 μL, 1.16 mmol). The mixture was stirred at ambient temperature for 2 h and then poured into quickly stirring water. The mixture was extracted with dichloromethane (3×50 ml) and concentrated in vacuo to give a residue. Flash chromatography of the residue on silica (eluent: 0-100% ethyl acetate in heptane) gave (S)-3-[1-(1,3-dioxo-1,3-dihydroisoindol-2-yl)isoquinolin-6-yloxy]piperidine-1-carboxylic acid tert-butyl ester (390 mg) E1l-MS: m/z=474.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[O:27]=[C:28]1[CH2:32][S:31][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39]([NH:41][S:42]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[O:40])[CH2:35][CH2:34]2)=[N:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:32]3[S:31][C:30]([N:33]4[CH2:34][CH2:35][CH:36]([C:39]([NH:41][S:42]([N:45]5[CH2:49][CH2:48][CH2:47][CH2:46]5)(=[O:44])=[O:43])=[O:40])[CH2:37][CH2:38]4)=[N:29][C:28]3=[O:27])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1CSC(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)=N1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1N=C(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
Pyrrolidine-1-sulfonic acid (1-{5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amide was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and Pyrrolidine-1-sulfonic acid [1-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carbonyl]-amide following General Procedure E.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14]OC)[C:9](=[O:17])[CH:8]=2)[CH:6]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[C:27][Si](C)(C)C)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[C:27][C:2]2[N:3]=[C:4]([CH3:18])[N:5]([C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:9](=[O:17])[CH:8]=3)[CH:6]=2)[CH:23]=[CH:22][N:21]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: COCCn1ncc(-n2cc(I)nc2C)cc1=O
Product: CCn1ncc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=370.1, 372.1 (M+H+), was prepared in accordance with the general method of example 35 from 5-(4-Iodo-2-methyl-imidazol-1-yl)-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 2-chloro-4-trimethylsilanylethynyl-pyridine.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(N(CC)CC)C.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:34].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzo-thiophene-2-carboxamide hydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) of N,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and 16.61 (0.21 mmol) of methanesulfonyl chloride are added and the mixture is stirred at room temperature for 16 h. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 1N aqueous hydrochloric acid and acetonitrile, then reconcentrated and dried under high vacuum. 15 mg (33.8% of theory) of the title compound are obtained.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23][S:24][CH3:25])=[O:10].[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:13][C:12]=3[CH2:22][CH2:23][S:24][CH3:25])=[O:10])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CSCCc1nc(-c2ccccc2)oc1C(=O)ON1C(=O)CCC1=O
Product: CSCCc1nc(-c2ccccc2)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3S (m/e) 424, obsd 425 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:19](Br)[CH:20]=[CH2:21]>>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:21][CH:20]=[CH2:19])[C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCCN12
Product: C=CCN1C(=O)N2CCCN=C2c2cc([N+](=O)[O-])ccc21

Procedure:
Preparation analogously to Example 29 from 10-nitro-6-oxo-2,3,4,5,6,7-hexahydropyrimido-[1,2-c]-quinazoline and allyl bromide.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=[N:19][OH:20]
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(C=NO)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a stirred suspension of 1-Methyl-1H-benzoimidazole-2-carbaldehyde (980 mg, 6.61 mmol) in H2O (10 ml) was added a solution of Sodium Acetate (3.25 g, 39.68 mmol) and Hydroxylamine hydrochloride (1.38 g, 19.84 mmol) in 10 ml of H2O. The reaction was stirred at rt for 2 hr and the thick precipitate was collected by filtration, washed with water and dried under vacuum to give 1.02 g (94%) of a white solid. 1H NMR (DMSO-d6) δ 12.06 (1H, s), 8.28 (1H, s), 7.65 (1H, d, J=7.5 Hz), 7.60 (1H, d, J=6.8 Hz), 7.32 (1H, t, J=7.2 Hz), 7.23 (1H, t, J=6.8 Hz), 4.00 (3H, s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:53]=[C:54]([CH2:59][CH:60]([C:62]2[N:63]=[CH:64][S:65][C:66]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[CH3:73])[NH2:61])[CH:55]=[C:56]([F:58])[CH:57]=1>CN(C=O)C>[F:51][C:52]1[CH:53]=[C:54]([CH2:59][CH:60]([NH:61][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[C:62]2[N:63]=[CH:64][S:65][C:66]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[CH3:73])[CH:55]=[C:56]([F:58])[CH:57]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: Cc1ccccc1-c1scnc1C(N)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1scnc1C(Cc1cc(F)cc(F)c1)NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 13D (33.1 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.89 (d, J=8.3 Hz, 1H), 7.35-7.16 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.99 (t, J=9.5 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.51 (d, J=6.4 Hz, 2H), 4.83-4.77 (m, 1H), 4.72 (s, 2H), 3.05 (d, J=7.7 Hz, 2H), 2.46-2.21 (m, 4H), 1.87 (s, 3H), 1.61 (s, 4H). MS (m/z) 561 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](O)([CH3:23])[CH3:22])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3=[C:13]([C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]2([CH3:23])[CH3:22])[CH:14]=1
Reactant: CC(C)(O)c1ccccc1-n1c2ccccc2c2cc(Br)ccc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Temperature: 60 °C

Procedure:
16.3 g (44 mmol) of 2-[2-(3-bromocarbazol-9-yl)phenyl]propan-2-ol are dissolved in 1200 ml of degassed toluene, a suspension of 40 g of polyphosphoric acid and 28 ml of methanesulfonic acid is added, and the mixture is heated at 60° C. for 1 h. The batch is cooled, and water is added. A solid precipitates out and is dissolved in CH2Cl2/THF (1:1). The solution is carefully rendered alkaline using 20% NaOH, and the phases are separated and dried over MgSO4. The solid obtained is washed by stirring with heptane. Yield: 13.5 g (37 mmol), 87% of theory, purity according to 1H-NMR about 95%.