Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)[O:35][C@H:34]([CH2:36]O)[CH2:33][O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:36][C@@H:34]([OH:35])[CH2:33][OH:32])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OC[C@H](O)COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
Nitrogen was bubbled to a solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazol-7-ol (Preparation 43C, 0.021 ml, 0.169 mmol) and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (0.021 ml, 0.169 mmol) in THF (2.5 ml) at room temperature for two min. To this mixture was added triphenylphosphine (0.044 g, 0.169 mmol) in one portion. Nitrogen was bubbled for two more minutes followed by the addition of diethyl azodicarboxylate (0.027 ml, 0.169 mmol) dropwise. The reaction vessel was immersed in a preheated oil bath held at 65° C., heated for 3 h., cooled, and concentrated under reduced pressure. The residue was extracted with ether and washed with water. The aqueous layer was re-extracted with ether and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated, and dried in vacuo. The residue was taken in 2 ml of acetic acid, cooled to 0° C. and treated with 1 ml 1N HCl. The reaction mixture was stirred at 0° C. for 30 min., concentrated under reduced pressure, and purified by silica gel column chromatography using hexane/ethyl acetate (0 to 30%) to yield (S)-3-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazol-7-yloxy)propane-1,2-diol (4.3 mg, 8.92 μmol, 11.84% yield) as a clear oil. The compound had an HPLC retention time of 9.39 min (Condition: Column: Sunfire C18 3.5 um, 3.0×150 mm; (15 min); solvent A: 95/5 water/MeCN with 0.05% TFA; solvent B: 5/95 water/MeCN with 0.05% TFA; Start % B=10 to Final % B=100; Wavelength=220 nm). LC/MS M+1=473.27. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58-7.68 (5H, m), 7.45 (1H, d, J=8.36 Hz), 7.02 (1H, d, J=2.42 Hz), 6.94 (1H, dd, J=8.36, 2.42 Hz), 4.99 (1H, d, J=5.06 Hz), 4.70 (1H, t, J=5.61 Hz), 4.02-4.09 (1H, m), 3.88-3.95 (1H, m), 3.74-3.84 (1H, m), 3.42-3.50 (2H, m), 3.14 (2H, t, J=7.92 Hz), 2.90-3.00 (2H, m).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][C@@H:5]([CH2:8][OH:9])[O:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([NH:18][CH3:19])[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCO.CCOCC.O>[Cl:10][C:11]1[N:12]=[C:13]([NH:18][CH3:19])[N:14]=[C:15]([N:7]2[C@H:2]([CH3:1])[CH2:3][O:4][C@H:5]([CH2:8][OH:9])[CH2:6]2)[CH:16]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CO[C@H](CO)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Yield: 55.9 %

Procedure:
A mixture of [(2S,5R)-5-methyl-2-morpholinyl]methanol (11.50 g, 65.2 mmol), 4,6-dichloro-N-methyl-2-pyrimidinamine (11.38 g, 63.9 mmol), and K2CO3 (19.87 g, 144 mmol) in EtOH (250 mL) was stirred at reflux under nitrogen for 23 hours. The mixture was cooled, poured into water (500 mL), and extracted with CH2Cl2 (3×400 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give a cream solid. The residue was purified by flash chromatography (400 g SiO2, 10-60% EtOAc in hexanes gradient). The product was collected and concentrated in vacuo to give a very sticky foam. The residue was taken up in Et2O (250 mL) and HCl (4.0 M in 1,4-dioxane, 10 mL) was added dropwise while the mixture was swirled. The solid that formed was collected by vacuum filtration and dried in the vacuum oven overnight to give a hydrochloride salt of the title compound (9.75 g) as a white solid. LC-MS (ES) m/z=273, 275 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].[C:10](Cl)(=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])#[N:9]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1nsc(N)c1C#N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nsc(NC(=O)CC(C)C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (6.38 g, 45.9 mmol) in pyridine (20 mL) at 0° C., isovaleryl chloride (6.65 g, 55 mmol) was added dropwise. After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The TLC and the MS showed the complete disappearance of the starting material and the reaction mixture was diluted with CHCl3 (200 mL), washed with water (200 mL), 2N HCl (225 mL), satd. NaHCO3 (200 mL), brine (200 mL) and dried over Na2SO4. Concentration of the CHCl3 layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate N-(4-cyano-3-methyl-isothiazol-5-yl)-3-methyl-butyramide (8.1 g, 79%) as an off-white crystalline solid. 1H NMR (300 MHz) δ 1.04 (d, 6H), 2.18-2.32 (m, 1H), 2.46 (d, 2H), 2.53 (s, 3H), 9.87 (bs, 1H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:45])[C@@H:30]([NH:35][C:36]([N:38]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C@@H:30]([NH:35][C:36]([N:38]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:45])[CH2:25][CH2:24]2)=[CH:13][CH:12]=1
Reactant: CC(C)CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCN(c1ccc(N)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reaction time: 1.25 h
Yield: 93 %

Procedure:
[(S)-{4-[(1-{2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoyl}-piperidin-4-yl)-(3-methyl-butyl)-amino]-phenyl}-carbamic acid benzyl ester] (Example 34, 2.75 g, 4.34 mmol) was dissolved in THF/MeOH (50 mL, 1:1), treated with 20% Pd/C (0.26 g), and shaken under H2 (49 psi) for 1.25 hours. The reaction was filtered through Celite and concentrated to give 2.01 g (93%) of the desired product.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4].[OH-].[Na+].[S:10](=O)([OH:12])[O-:11].[Na+]>>[CH3:7][CH:6]1[CH:2]([CH3:1])[C:3](=[O:5])[O:4][S:10]1(=[O:12])=[O:11]
Reactant: O=S([O-])O
Reactant: C/C=C(\C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1C(=O)OS(=O)(=O)C1C

Procedure:
100 g. of α-methyl-crotonic acid is reacted with sodium hydroxide to neutralize the carboxyl group. Sodium bisulfite (104 g.) in aqueous solution is added and the reaction continued as described in earlier examples to obtain 3,4-dimethyl-1,2-oxathiolane-5-one-2,2-dioxide.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl[CH2:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:12]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: ClCc1ccsc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(OCc2ccsc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 3-chloromethyl-thiophene [CAS 2746-23-8], and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 389.2
Reaction SMILES: O1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[N:7]1([CH2:12][C:13]2C=CC(NN)=C[CH:14]=2)C=NC=N1>O1CCOCC1.O>[NH:7]1[C:12]2[C:4](=[CH:5][CH:6]=[CH:14][CH:13]=2)[CH:3]=[CH:2]1
Reactant: C1=COCCC1
Reactant: NNc1ccc(Cn2cncn2)cc1
Solvent: O
Solvent: C1COCCO1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 37.2 %

Procedure:
3,4-Dihydro-2H-pyran (3.9 ml, 42.7 mmol) was added to a stirred solution of 4-(1,2,4-triazol-1-ylmethyl)phenyl hydrazine (EP 497,512; 4.0 g, 21.1 mmol) in dioxane/water/5N HCl (38 ml/14 ml/4.7 ml) and stirred at room temperature for 1.75 h. The solution was then refluxed for 1.5 h and the solvent removed under vaccum. The residue was taken up into CH2 Cl2 and saturated aqueous K2CO3 solution. The aqueous was separated and further extracted with CH2Cl2 (×4). The combined organic extracts were dried (MgSO4) and evaporated and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (80:8:1) to give the title-indole (0.919 g, 17%), δ (250 MHz, CDCl3) 1.91-2.03 (2H, m, CH2), 2.84 (2H, t, J=7.9Hz, CH2), 3.73 (2H, t, J=7.9Hz, CH2), 5.43 (2H, s, CH2), 7.04 (1H, d, J=2.3Hz, Ar-H), 7.11 (1H, dd, J=2.3 and 8.3Hz, Ar-H), 7.35 (1H, d, J=8.3Hz, Ar-H), 7.58 (1H, s, Ar-H), 7.97 (1H, s, Ar-H), 8.02 (1H, s, Ar-H), 8.18 (1H, s, NH).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[SiH:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9]>N1C=CC=CC=1C1C(C2C=CC=CN=2)=CC=CN=1.C[Si](C[Fe]C[Si](C)(C)C)(C)C.C1(C)C=CC=CC=1>[Si:7]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: C=CCCCC
Reactant: CC[SiH](CC)CC
Agent: C[Si](C)(C)C[Fe]C[Si](C)(C)C
Agent: c1ccc(-c2cccnc2-c2ccccn2)nc1
Solvent: Cc1ccccc1
Product: CCCCC=C[Si](CC)(CC)CC
Reaction time: 4 h
Yield: 5 %

Procedure:
A stock solution containing 5 mg of bis[(trimethylsilyl)methyl]iron(II) terpyridine and 0.60 g of toluene was charged into a scintillation vial in a nitrogen filled drybox. The toluene was removed in vacuo followed by addition of 0.114 g (1.4 mmol) of 1-hexene. To the same vial, 0.105 g (0.90 mmol) of Et3SiH was added. The vial was sealed with a small amount Krytox grease and electrical tape, removed from the drybox and placed in a 95° C. oil bath. The concentration of the iron complex was less than 0.1 mol % relative to the silane, and the reaction time was 4 hours to achieve greater than 90% conversion to (CH3CH2)3Si—(CH2)5—CH3. Less than 5% each of (CH3CH2)3Si—CH═CH—(CH2)3—CH3 and (CH3CH2)2(H)Si—(CH2)5—CH3 were formed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:68]1([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:71]3[CH2:72][CH2:73][N:68]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:69][CH2:70]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.65 mmol) in 10 ml of anhydrous DMF were added HATU (296 mg, 0.78 mmol) and N,N-diisopropylethylamine (185 mg, 1.43 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of tert-butyl 1-piperazinecarboxylate (182 mg, 0.98 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 1M HCl was added slowly until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazine-1-carboxylate as white solid. Yield: 290 mg, 84%.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14](/[C:16](=[CH:19]\[CH3:20])/[CH:17]=O)[CH3:15]>C1C=CC=CC=1.O>[CH2:19](/[C:16](=[CH:14]\[CH3:15])/[CH:17]=[CH:5]/[C:3]#[N:4])[CH3:20]
Reactant: C/C=C(/C=O)CC
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C/C=C(/C=C/C#N)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a mixture of sodium hydride (60% in oil, 7.5 g) and dry benzene (200 ml) was added dropwise diethyl cyanomethylphosphonate (30 g) with stirring at 0° C. under dry nitrogen atmosphere. After stirring for 60 minutes at room temperature, a solution of (E)-2-ethyl-2-butenal (16.6 g) in dry benzene was added thereto at 0° C. with stirring. The resulting mixture was allowed to stand at room temperature for 60 minutes and diluted with water and then extracted with ethyl acetate. The extract was washed successively with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave an oil which was purified by distillation under reduced pressure to give (E,E)-4-ethyl-2,4-hexadienenitrile (8.4 g).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([CH3:34])([CH3:33])[CH2:19][S:20](=[O:32])(=[O:31])[NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCOCC1>CN(C=O)C>[CH:28]([N:25]1[CH2:26][CH2:27][CH:22]([NH:21][S:20]([CH2:19][C:18]([NH2:17])([CH3:33])[CH3:34])(=[O:32])=[O:31])[CH2:23][CH2:24]1)([CH3:30])[CH3:29]
Reactant: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
607 mg (1.2 mmol) of crude [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester were dissolved in 6 ml DMF. 1.5 ml morpholine were added and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and co-distilled three times with 20 ml DMF to give crude 2-amino-2-methyl-propane-1-sulfonicacid (1-isopropyl-piperidin-4-yl)-amide as yellow oil. Yield: 360 mg MS (ES+): m/e=278.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[S:3].O1CCCC1.[CH3:18][CH:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23]1)[CH3:20]>C(O)C>[CH3:20][CH:19]([N:21]([CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:27]1)[C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[S:3])[CH3:18]
Reactant: CC(C)NC1CCN(CCc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N(C(=S)Nc1ccccc1[N+](=O)[O-])C1CCN(CCc2ccccc2)CC1
Yield: 84 %

Procedure:
A mixture of 21.6 parts of 1-isothiocyanato-2-nitrobenzene and 45 parts of tetrahydrofuran is stirred till all solid enters solution. Then there are added 29.5 parts of N-(1-methylethyl)-1-(2-phenylethyl)-4-piperidinamine and 160 parts of ethanol and the whole is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 43 parts (84%) of N-(1-methylethyl)-N'-(2-nitrophenyl)-N-[1-(2-phenylethyl)-4-piperidinyl]thiourea; mp. 100.6° C.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].ClCCl>[CH3:1][C:2]1[NH:6][C:7]2[C:12]([C:3]=1[CH3:4])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Nc1ccccc1
Reactant: C#CC(C)O
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: ClCCl
Product: Cc1[nH]c2ccccc2c1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
3-Butine-2-ol (0.701 g, 10 mmol), aniline (0.931 g, 10 mmol), Ru3(CO)12 (32.0 mg, 0.05 mmol) and aniline hydrochloride (0.259 g, 2.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 120° C. for 12 hours. After cooling, dichloromethane (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby 2,3-dimethyl indole (1.31 g; 9.0 mmol; yield, 90%; purity, about 99%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>CN1CCCC1=O>[C:20]1([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-amino-2-methoxy-pyridine (30 mg, 0.24 mmol) and potassium carbonate (167 mg, 1.20 mmol) are dissolved in N-methyl 2-pyrrolidone (1 ml). Phenyl chloroformate (36 μl, 0.29 mmol) is added and the reaction mixture is stirred at room temperature for 2 hours.
Reaction SMILES: [C:1]1([C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=2)=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6](=[N:24][OH:25])[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(C(=O)c2cccs2)c2ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)COc1ccc(C(=NO)c2cccs2)c2ccccc12
Yield: 95 %

Procedure:
5 g [4-(2-thenoyl)-1-naphthyloxy]-acetic acid are dissolved in 50 ml pyridine. 1.5 g hydroxylamine hydrochloride are introduced in solution and the mixture maintained at reflux temperature for 12 hours. The solvent is then removed under reduced pressure, the residue washed with a dilute aqueous hydrochloric acid solution; the oxime obtained with a 95% yield, which is a mixture of two stereoisomers, melts at 215° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:19]([NH2:21])[CH3:20])=[C:10]([C:13]3[C:14]([CH3:18])=[N:15][NH:16][CH:17]=3)[CH:11]=2)[CH:6]=[CH:5]1.Cl[C:23]1[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[N:26]=[C:25]([S:32][CH3:33])[N:24]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:31][C:27]1[C:28]([C:29]#[N:30])=[C:23]([NH:21][C@H:19]([C:9]2[N:8]=[C:7]3[CH:6]=[CH:5][N:4]([CH3:3])[C:12]3=[CH:11][C:10]=2[C:13]2[C:14]([CH3:18])=[N:15][NH:16][CH:17]=2)[CH3:20])[N:24]=[C:25]([S:32][CH3:33])[N:26]=1
Reactant: Cc1n[nH]cc1-c1cc2c(ccn2C)nc1[C@H](C)N
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2c[nH]nc2C)n1

Procedure:
A solution of (S)-1-(1-methyl-6-(3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine dihydrochloride (200 mg, 0.609 mmol), 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (182 mg, 0.914 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.318 mL, 1.83 mmol) in acetonitrile (5 mL) was heated in a microwave reactor at 120° C. for 2 hours. The mixture was then concentrated. The residue was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by column chromatography eluting with 20-80% EtOAc in hexane over 60 minutes to give the title compound. ESI-MS m/z [M+H]+ calc'd for C21H22N8S, 419; found 419.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]=3[N:15]=[C:14](Cl)[C:13]=2[CH2:12][CH2:11]1.[CH3:30][NH2:31]>O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]=3[N:15]=[C:14]([NH:31][CH3:30])[C:13]=2[CH2:12][CH2:11]1
Reactant: COc1ccc(N2CCc3c(Cl)nc4c(OCC(F)(F)F)cccc4c32)c(C)c1
Reactant: CN
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccc(OC)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.42 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) in the pressure tube, and the reaction mixture was refluxed at 180° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:2) to obtain 450 mg of desired compound as solid in 76% of yield.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:28]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32](O)=[O:33])=[C:24]2[C:23](=[O:49])[N:22]([CH3:50])[C:21]1=[O:51])[CH:17]([CH3:19])[CH3:18].CN>C1COCC1.O>[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:28]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:3][CH3:1])=[O:33])=[C:24]2[C:23](=[O:49])[N:22]([CH3:50])[C:21]1=[O:51])[CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2cccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.04 mL) followed by isobutylchloroformate (0.033 g) were added to a solution of 3-[7-isobutyl-5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.08 g) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Methylamine (2M, 2 mL) was added and the mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. Reaction was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on preparative HPLC to give the title compound (0.027 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH:14]1(C(O)=O)[CH2:17][CH2:16][CH2:15]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:14]1[CH2:17][CH2:16][CH2:15]1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=C(O)C1CCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cc(C2CCC2)c(Cl)nn1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
3,6-Dichloropyridazine (10 g) was suspended in water (200 ml), H2SO4 (19.7 g) and cyclobutane carboxylic acid (32.7 g) were added and the reaction degassed under N2 at 70° C. Silver nitrate (2.28 g) was added followed by dropwise addition of ammonium persulfate (45.9 g) in water (120 ml). After an additional 1 hour heating at 70° C., the reaction was poured onto ice, basified to pH 8-9 with aqueous ammonium hydroxide and extracted into ethyl acetate (3×500 ml), dried (MgSO4) and evaporated to dryness. Purified with hexane-ethyl acetate mixtures to obtain pure product (13.4 g). 1H NMR (360 MHz , CDCl3) δ 1.57 (2H, m), 1.82 (4H, m), 2.20 (1H, m), 3.30 (1H, m), 7.38 (1H, s); MS (ES+) m/e 217 [MH]+.