Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(OCC)(=O)C.Cl>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(CCNc2ccc(Br)cn2)cc1
Yield: 80 %

Procedure:
A mixture of 2,5-dibromo-pyridine (5 g; 21.10 mmol) and tyramine (5.79 g; 42.21 mmol) was heated at 200C for 1 hour. Upon cooling the residue was taken up into ethyl acetate, water and 1N HCl. The phases were separated and the organic phase was washed twice with 1N HCl. The combined aqueous phases were basified to pH-9 with 2N NaOH and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to afford 4-{2-[(5-bromopyridin-2-yl)amino]ethyl}phenol as a beige solid (5 g; 80% yield), which was used in the next step without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[C:21]1[N:22]=[N:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:28][CH:27]=2)[CH:25]=1.Cl.Cl.[NH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45]([CH3:49])[CH2:44]1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1COCC1.CN(C=O)C.C(Cl)Cl>[CH3:49][N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([NH:42][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[N:22]=[N:23][N:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[CH:25]=2)[CH2:44]1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Reactant: CN1CCCC(N)C1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCCC(Nc2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)C1
Temperature: 70 °C
Yield: 5 %

Procedure:
LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) was added to a degassed suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (200 mg; 0.44 mmol; 1.0 eq.), 3-Amino-1-methylpiperidine dihydrochloride, 98% (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (7.0 mg; 0.01 mmol; 0.02 eq.) and dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) in DMF (500 μl). The reaction mixture was then heated at 70° C. O/N. As the reaction was not completed, further 3-Amino-1-methylpiperidine dihydrochloride (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (7.0 mg; 0.01 mmol; 0.02 eq.), dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) and LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) were added and the reaction mixture was heated again at 70° C. for 12 h. It was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a brown solid (10 mg; 5%). 1H NMR (300 MHz, DMSO-d6-d6): 12.96 (brs, 1H), 9.26 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.36-7.33 (m, 1H), 6.96-6.92 (m, 2H), 5.36 (m, 1H), 3.64-3.55 (m, 1H), 3.00 (m, 1H), 2.73 (m, 1H), 2.23 (m, 3H), 1.99-1.59 (m, 3H), 1.30 (m, 1H). HPLC (max plot) 94.3%; Rt % 1.99 min. UPLC/MS: (MS+) 487.3, (MS−) 485.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1.[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:7]([O:8][CH2:23][C:22]#[CH:21])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1
Reactant: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)cc(F)c(-n2nnn(CCCF)c2=O)c1N
Yield: 104.8 %

Procedure:
The mixture of 1-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-4-(3-fluoropropyl)-tetrazolinone (0.28 g), propargyl bromide (0.13 g), and potassium carbonate (0.14 g) in acetonitrile (5 ml) was heated under reflux for 0.5 hour. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the desired product (0.33 g).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C(O)CO>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[CH:19]=[CH:20][CH:21]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1cccc(F)c1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cccc(F)c1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 3-fluoroaniline (9f, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10f as pure product. To a solution of 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10f, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 86 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1e (220 mg, 80%); mp: 130-132° C.; 1H NMR (300 MHz, CDCl3) δ 10.62 (s, 1H), 8.31 (dd, J=3.0, 1.7 Hz, 1H), 7.83 (dd, J=3.0, 1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.53 (m, 2H), 7.36-7.18 (m, 3H), 7.12 (t, J=7.5 Hz, 1H), 6.99-6.91 (m, 5H), 6.71-6.66 (m, 2H), 5.48 (s, 2H), 4.66 ppm (d, J=5.6 Hz, 2H); MS (ESI m/z): 495 [M+H]+. Yield: 80%
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].[C:14]([C:18]1[CH:19]=[CH:20][C:21]([S:25]([CH3:27])=[O:26])=[C:22]([NH2:24])[CH:23]=1)([CH3:17])([CH3:16])[CH3:15].N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-]>>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([NH:24][C:22]1[CH:23]=[C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])[CH:19]=[CH:20][C:21]=1[S:25]([CH3:27])=[O:26])=[O:9])=[N+:2]=[N-:3]
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: CS(=O)c1ccc(C(C)(C)C)cc1N
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: Cc1ccc(C(=O)Nc2cc(C(C)(C)C)ccc2S(C)=O)cc1N=[N+]=[N-]

Procedure:
3-Azido-N-(5-tert-butyl-2-methanesulfinyl-phenyl)-4-methyl-benzamide was prepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and 5-tert-butyl-2-methanesulfinyl-phenylamine in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: [CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@:6]1([CH3:28])[CH2:22][O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:5]1[CH2:4][CH2:3]2.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O>[CH3:30][C:29]([O:21][C@@H:16]1[CH2:17][O:18][C:19](/[C:15]/1=[CH:14]/[CH2:13][C@H:12]1[C@:2]2([CH3:1])[CH2:3][CH2:4][C@H:5]3[O:25][C:24]([CH3:27])([CH3:26])[O:23][CH2:22][C@@:6]3([CH3:28])[C@H:7]2[CH2:8][CH2:9][C:10]1=[CH2:11])=[O:20])=[O:31]
Reactant: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
3,19-Isopropylidene andrographolide (15 g) obtained in step 1 was refluxed in distilled acetic anhydride (110 ml) for 45 min. After confirming the complete formation of the product (by TLC analysis), the contents were cooled to room temperature, diluted with water (500 ml) and extracted with dichloromethane (3×200 ml). The organic layer was separated and dried over Na2SO4 and concentrated to get a brown oily material. The crude material was purified by flash column chromatography (silica gel 230-400 mesh; 250 g, eluting system light petrol: ethyl acetate=85:15) to obtain pure 14-acetyl-3,19-isopropylidene andrographolide (13 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:28]([O-])=O)=[C:12]([CH:15]=[C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH3:20])[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:28][C:11]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[CH:17][C:16]([NH:18][C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH3:20])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](Nc1cc(C#N)c([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1cc(C#N)c(N)c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)-2-nitrobenzonitrile (Method 97, 4.20 g, 10.0 mmol) and zinc dust (3.40 g, 52 mmol) in MeOH-THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40 ml). The reaction mixture was stirred at 25° C. for 1 hour, to which was then added saturated ammonium acetate solution (50 ml). The resulting mixture was stirred for another 30 minutes. Zn dust was removed by filtration and washed with EtOAc (200 ml). The organic layer was separated, washed with brine (100 ml), dried over sodium sulfate, and concentrated. The crude product was used directly for the next step without further purification. MS: Calcd: 376; Found: [M+H]+ 377.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1cccc2sc(CO)c(Br)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc2sc(C=O)c(Br)c12

Procedure:
At room temperature, a solution of (3-bromo-4-methyl-benzo[b]thiophen-2-yl)-methanol (23d) (400 mg, 1.55 mmol) and manganese dioxide (652 mg, 7.5 mmol) in dichloromethane (20 mL) was stirred for 2 hours. The mixture was then filtered and evaporated under reduced pressure to afford the desired aldehyde (23e) as a white solid without further purification (310 mg, 1.21 mmol, 78%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:28])[C:14](=[O:27])[N:15]([CH3:26])[C:16]2=[O:25])=[CH:11]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:28])[C:14](=[O:27])[N:15]([CH3:26])[C:16]2=[O:25])=[CH:11]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[2-(1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-ethyl]-carbamic acid tert-butyl ester (step 4) (1.11 g, 2.79 mmol) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (2.1 mL, 25.1 mmol). The reaction was stirred at RT for 4 h. The reaction was quenched by pouring into stirring 2M NaOH and further NaOH added until alkaline to pH paper. The layers were separated and the aqueous phase extracted with DCM (3×75 mL). The combined organic phases were washed with water (100 mL), brine (75 mL) and passed through a hydrophobic frit. The solvent was removed under reduced pressure, affording the title compound as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:19](F)(F)S(OC)(=O)=O>ClCCl>[CH3:19][N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.1 %

Procedure:
To a solution of ethyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (1000 mg, 5.0 mmol) in dichloromethane (10 mL) was added methyl trifluoromethanesulfonate (1200 mg, 7.3 mmol). The red solution was stirred at room temperature. After 14 h, the mixture was partitioned between dichloromethane and NaHCO3 (sat). The aqueous was extracted with dichloromethane (2×). The combined organic was dried over Na2SO4, concentrated and purified on silica. The product was triturated with EtOAc-hexane-CHCl3 to give the pure product as crystals (260 mg, 21%). Calc'd for C12H12N2O3, 232.08; MS (ESI pos. ion) m/z: 233 (MH+). 1H NMR (400 MHz, CHLOROFORM-d): 1.36 (t, J=7.04 Hz, 3 H), 3.39 (s, 3 H), 4.32 (q, J=7.17 Hz, 2 H), 7.32 (d, J=7.43 Hz, 2 H), 7.42 (t, J=7.34 Hz, 1 H), 7.50 (t, J=7.73 Hz, 2 H), 7.99 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([C:13]#[N:14])[CH3:12])[CH:6]=1)[CH3:2].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]#[N:14])([CH3:18])[CH3:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C(C)C#N)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C(C)(C)C#N)c1
Reaction time: 16 h

Procedure:
3-(1-Cyano-ethyl)-benzoic acid ethyl ester were dissolved in 4 ml dry DMF. Under nitrogen atmosphere, 138 mg of 60% sodium hydride and 423 mg methyl iodide were added at RT. The mixture was stirred for 16 hrs, then quenched by addition of 1 ml methanol and evaporated. The residue was purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH2:42](I)[CH2:43][CH3:44]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH2:42][CH2:43][CH3:44])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: CCCI
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Product: CCCc1cc2ccn3c(=O)c(-c4ccc(OCc5ccccc5)cc4)cc(C(=O)N(CCOC)c4ccccc4)c3c2s1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with propyl iodide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:13]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[Br:33]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:33][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)n1

Procedure:
Reaction Scheme 13 provides an example for the preparation of 2,6-di-tert-butylisonicotinic acid (Compound C3) which is a reagent in accordance with Formula 8 for the preparation of several preferred compounds of the present invention. Thus, 2,6-di-tert-butyl-4-methylpyridine (available commercially from Aldrich Chemical Co.) is reacted with N-bromosuccinimide and benzoyl peroxide to provide 4-bromomethyl-2,6-di-tert-butylpyridine (Compound A3). Compound A3 is reacted with base (sodium hydroxyde) to yield the coresponding hydroxymethyl compound (Compound B3), which is thereafter oxidized in a Jones oxidation reaction to give 2,6-di-tert-butylisonicotinic acid (Compound C3). ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].I[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[N:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Reactant: Ic1cnc2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cnc3ccccn23)cc1OC(C)c1ccccc1Cl

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.0 Eq.), 3-Iodo-imidazo[1,2-a]pyridine (108 mg, 0.44 mmol, 1.2 Eq.) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.55 mL, 1.10 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% EtOAc/petroleum Ether) to give the sub-title compound as am off-white solid (61 mg, 0.15 mmol, 40%); 1H NMR (400 MHz, CDCl3) δ 1.77 (3H, d), 3.96 (3H, s), 5.86 (1H, q), 6.89 (1H, s), 7.28-7.43 (4H, m), 7.67 (1H, dd), 7.72-7.78 (1H, m), 7.83 (1H, s), 8.32 (2H, d).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:26])[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:27]([CH2:29][NH2:30])[OH:28]>>[OH:28][CH2:27][CH2:29][NH:30][C:23](=[O:25])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:9]3[CH:8]=[C:7]([CH3:26])[N:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:10]=3)[O:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: NCCO
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(CC(C)C)n1
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)NCCO)cc3)no2)cc(CC(C)C)n1

Procedure:
N-(2-Hydroxy-ethyl)-2-{4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide is prepared from {4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid and ethanolamine in analogy to Example 65; LC-MS: tR=0.77, [M+1]+=395.19.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:38]=C(C3CC3)N[N:35]=2)[C:30](=[O:42])[N:29]([CH3:43])[CH:28]=1)(=[O:3])[CH3:2].BrC1C=C(NC2C=[CH:62][C:61]3[CH2:60][N:59]([CH3:64])[CH2:58][CH2:57][C:56]=3N=2)C(=O)N(C)C=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1C(=O)C2SC3CCCCC=3C=2CC1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:38]=[CH:62][C:61]3[CH2:60][N:59]([CH3:64])[CH2:58][CH2:57][C:56]=3[N:35]=2)[C:30](=[O:42])[N:29]([CH3:43])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 50 %

Procedure:
Following the procedures as described for 136e and starting with 5-bromo-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridine-2(1H)-one 205b and (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b, compound 223a was obtained in 50% yield.
Reaction SMILES: [C:1]1([CH:7]([NH2:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][CH2:13][NH:14][C:15]([NH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[CH:9])=[O:16]
Reactant: O=C=NCCCl
Reactant: C#CC(N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(NC(=O)NCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 180 mg of 1-phenyl-prop-2-ynylamine (Formula 28) in 5 mL of CH2Cl2 were added 0.1 mL of 2-chloroethyl isocyanate and 0.2 mL of triethylamine. After the mixture was stirred at room temperature for 2 hours, the solvent was removed. Column chromatography (50% ethyl acetate/hexane) gave 153 mg of 1-(2-chloro-ethyl)-3-(1-phenyl-prop-2-ynyl)-urea (Formula 29) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.46 (m, 1H), 3.45-3.49 (m, 2H), 3.52-3.54 (m, 2H), 5.40-5.41 (m, 1H), 5.55-5.57 (m, 1H), 5.74-5.76 (m, 1H), 7.27-7.35 (m, 3H), 7.48-7.50 (m, 2H).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[C:5]([O:8][CH3:9])(=[O:7])[CH3:6]>>[CH3:1][O:4][CH2:2][CH2:3][CH2:9][O:8][C:5](=[O:7])[CH3:6]
Reactant: COC(C)=O
Reactant: CC1CO1
Product: COCCCOC(C)=O

Procedure:
In a preferred reaction propylene oxide is reacted with methyl acetate to produce methoxypropylacetate.
Reaction SMILES: O1CCCC1.[CH:6]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18](Cl)=[N:19][OH:20])[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7]1.[C:22]([C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>O>[CH:6]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)[O:20][N:19]=2)[CH2:8][CH2:7]1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1cccc(OCC2CC2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2cccc(OCC3CC3)c2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-cyclopropylmethoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.624 mmol) described in Manufacturing Example 66-1-4 and 3-ethynyl-pyridin-2-ylamine (47 mg, 0.398 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (220 μL, 1.56 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (26 mg, 13%).