Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:18]2[CH2:17][CH:16]=[CH:15][C:14](=[O:19])[NH:13][C:12]=2[C:11]([F:20])=[CH:10][C:9]=1[F:21].Br[C:23]1C(F)=C(F)C=C(F)[C:24]=1N.CNCCNC.C(Br)=C>[Cu]I.C1(C)C=CC=CC=1>[F:7][C:8]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[N:13]([CH:23]=[CH2:24])[C:12]=2[C:11]([F:20])=[CH:10][C:9]=1[F:21]
Reactant: Nc1c(F)cc(F)c(F)c1Br
Reactant: O=C1C=CCc2c(F)c(F)cc(F)c2N1
Agent: [Cu]I
Agent: C=CBr
Agent: CNCCNC
Solvent: Cc1ccccc1
Product: C=CN1C(=O)CCCc2c(F)c(F)cc(F)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A heavy-walled sealable 100 mL tube containing copper (I) iodide (0.088 g, 0.46 mmol), potassium carbonate (1.57 g, 11.4 mmol) and 6,7,9-trifluoro-1,5-dihydro-benzo[b]azepin-2-one (1.02 g, 4.74 mmol, prepared from commercially available 2-bromo-3,4,6-trifluoroaniline via application of Steps 1-3 of the procedure used for the synthesis of Examples 73 and 74) was fitted with a stirbar and septa and flushed with nitrogen. Toluene (5.0 mL), N,N′-dimethylethylene diamine (0.10 mL, 0.93 mmol) and vinyl bromide (10.0 mL, 1.0 M solution in tetrahydrofuran (THF), 10.0 mmol) were then added, in that order. The septa was removed, the reaction vessel was sealed tightly with a teflon screwcap and then placed in a pre-heated 110° C. oil bath. After 24 hours, the reaction was cooled to room temperature, poured into 1:1 H2O:saturated aqueous NaCl solution (50 mL) and extracted with methylene chloride (3×30 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 30% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Sc1ncnc2ccccc12
Product: c1ccc(CSc2ncnc3ccccc23)cc1
Yield: 47.8 %

Procedure:
The title compound(5.2 g) was prepared from 4-mercaptoquinazoline(7.0 g) and benzyl chloride(5.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>CN(C=O)C.CCOCC>[F:8][C:7]1[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:3][C:4]([O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:5][CH:6]=1
Reactant: COc1ccc(C=NOc2ncc(F)c(N)n2)cc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C=NOc2ncc(F)c(N=CN(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a magnetically stirred suspension of 4-methoxybenzaldehyde O-(4-amino-5-fluoropyrimidin-2-yl)oxime (0.075 g, 0.29 mmol) in anhydrous DMF (0.2 mL) was added DMF-DMA (0.068 g, 0.57 mmol) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with Et2O (10 mL) and then was cooled to 0° C. The resulting solid was collected by vacuum filtration, and the cake was washed with cold Et2O followed by hexanes. The precipitate that formed in the filtrate was collected by vacuum filtration and the combined solids were dried under vacuum to give N′-{5-fluoro-2-[1-(4-methoxyphenyl)-methylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.069 g, 76%) as a white solid: mp 243-245° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 3.82 (s, 3H), 3.21 (s, 3H), 3.10 (s, 3H); ESIMS m/z 318 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>CCOC(C)=O.Cl>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
To a stirring mixture of morpholine (1.00 g) and triethylamine (1.6 mL) in EtOAc (10 mL) at 0° C. is added chloroacetyl chloride (1.83 mL) dropwise. The mixture is stirred at 0° C. for 35 min., diluted with 10% HCl (25 mL) and extracted with EtOAc (3×50 mL). The organic layer is dried over MgSO4, and the solvent removed. The residue is purified by SiO2 flash column chromatography (eluent 35% EtOAc/hexane) to afford 1.42 g (76%) of the title compound as a yellow liquid. Physical characteristics: 1H NMR (CDCl3) δ 3.54, 3.64, 3.72, 4.07; IR (liq.) 2859, 1654, 1463, 1438, 1302, 1270, 1251, 1233, 1115, 1069, 1040, 965, 790, 657, 604 cm−1; MS (ESI+) m/z 164 (M+H)+. Anal. Found: C, 43.66; H, 6.17; N, 8.58.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=1)=[O:4].CN(C)/[CH:22]=[CH:23]/[C:24]([C:26]1[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=1)=O>COCCO>[CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:19]=[C:24]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=3)[CH:23]=[CH:22][N:18]=2)=[CH:12][CH:11]=1)=[O:4]
Reactant: CNC(=O)[C@H]1CCCN1c1ccc(NC(=N)N)cc1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Solvent: COCCO
Product: CNC(=O)[C@H]1CCCN1c1ccc(Nc2nccc(-c3cnc(C)n3C(C)C)n2)cc1
Temperature: 200 °C
Yield: 35 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid methylamide (Method 59; 0.27 g, 1.0 mmol) and of (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one, (Method 24 of WO 03/076436; 0.15 g, 0.0.68 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. The solvent was removed in vacuo and the gum was carefully chromatographed eluting with DCM, 1% MeOH/DCM, 2% MeOH/DCM and finally 3% MeOH/DCM to yield a yellow solid (101 mg, 35%). NMR (400.132 MHz, CDCl3) 8.28 (d, 1H), 7.39 (d, 2H), 7.34 (s, 1H), 6.89 (s, 1H), 6.83 (d, 1H), 6.61-6.57 (m, 3H), 5.62 (septet, 1H), 3.99 (t, 1H), 3.65 (t, 1H), 3.24-3.17 (m, 1H), 2.80 (d, 3H), 2.55 (s, 3H), 2.29-2.24 (m, 2H), 2.06-1.89 (m, 2H), 1.46 (d, 6H); m/z 420.
Reaction SMILES: N[C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[N:7]([CH2:18][CH3:19])[N:6]=1.C(ON=O)(C)(C)C>CN(C)C=O>[CH2:18]([N:7]1[C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:9][C:5]([O:4][C:3]2[CH:2]=[CH:23][C:22]([F:24])=[CH:21][CH:20]=2)=[N:6]1)[CH3:19]
Reactant: CCn1nc(Oc2ccc(F)cc2N)cc1-c1cccc(C#N)c1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: CCn1nc(Oc2ccc(F)cc2)cc1-c1cccc(C#N)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
A solution of 3-[3-(2-amino-4-fluorophenoxy)-1-ethyl-1H-pyrazol-5-yl]benzonitrile (262 mg, 0.813 mmol, 1 equiv) in N,N-dimethylformamide (2 mL) was added dropwise over 5 minutes to a solution of t-butylnitrite (0.15 mL, 1.2 mmol, 1.5 equiv) in N,N-dimethylformamide (2.5 mL) at 60° C. The reaction mixture was stirred at 60° C. for 20 minutes, then was partitioned between ethyl acetate and aqueous hydrochloric acid solution (1 M). The organic layer was washed sequentially with an additional portion of aqueous hydrochloric acid solution (1 M) and saturated aqueous sodium chloride solution. The washed organic layer was dried over sodium sulfate, and the dried solution was filtered. The filtrate was concentrated, and the residue was purified by flash-column chromatography on silica gel (hexanes, grading to 50% ethyl acetate-hexanes) to afford 3-[1-ethyl-3-(4-fluorophenoxy)-1H-pyrazol-5-yl]benzonitrile (127 mg, 51%) as a white solid. Calcd (M+1)+: 308.1. Found: 308.0.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[OH-].[Na+].[CH3:28]I>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:22][O:23][CH3:28])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CI
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(COC)cc2C)c1C
Reaction time: 0.08 h

Procedure:
To a solution of {4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol in dry THF was added 60% NaOH in oil and stirred for 5 min. Excess of MeI was added and stirred at room temperature for 2 hr. After standard worked up procedure and purification, the title compound was obtained as a clear golden oil. 1H NMR(CDCl3) d 7.02(s,2H), 6.06(s,1H), 4.40(s,3H), 3.72(d,1H), 3.39(s,3H), 3.36(m,1H), 2.12(s,3H), 2.11(s,3H), 2.10(s,6H), 1.4–1.7(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](O)=[O:8])(=O)[CH3:2].[NH2:14][N:15]1[C:27](=[O:28])[C:25]2[C:26]3[N:18]([C:19]([O:29][CH3:30])=[CH:20][C:21]=3[CH2:22][CH2:23][CH:24]=2)[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:16]1.P(Cl)(Cl)Cl.[P].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:30][O:29][C:19]1[N:18]2[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][N:15]([N:14]3[C:7](=[O:8])[C:6]4[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:4]=[C:1]3[CH3:2])[C:27](=[O:28])[C:25]3=[CH:24][CH2:23][CH2:22][C:21]([CH:20]=1)=[C:26]23
Reactant: COc1cc2c3n1C(c1ccccc1)=CN(N)C(=O)C3=CCC2
Reactant: CC(=O)Nc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: COc1cc2c3n1C(c1ccccc1)=CN(n1c(C)nc4ccccc4c1=O)C(=O)C3=CCC2
Temperature: 25 °C
Yield: 17.3 %

Procedure:
0.834 g (4.65 mmol) of acetylanthranilic acid and 1.3 g (4.23 mmol) of 3-amino-9-methoxy-1-phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one are dissolved in 13 ml of CH2Cl2, the mixture is stirred at room temperature and 0.7 g (5 mmol) of phosphorus trichloride is added. The mixture is stirred for 20 h and 0.35 g of phosphorus trichlonrde is added, followed by a fuirther 0.35 g 8 h later. The mixture is cooled, 50 ml of saturated NaHCO3 solution and 100 ml of CH2Cl2 are added and the organic phase is separated out after settling has taken place and washed with water. This solution is dried, evaporated and purified by chromatography in the mixture DM1. 0.33 g of yellow powder is obtained. M.p.=277° C.—Yld 17%.—TLC (DM3): Rf=0.47.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[C:6]([O:18][CH3:19])[CH:5]=1)#[N:2].[NH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>C(O)(=O)C>[CH3:16][N:15]([CH3:17])[C:13]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[C:1]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:2]=[C:10]2[OH:11])=[CH:5][C:6]=1[O:18][CH3:19])=[O:14]
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1C(=O)N(C)C
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(=O)N(C)C
Temperature: 130 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A mixture of 6-Cyanomethyl-4-methoxy-N,N-dimethyl-isophthalamic acid (2.0 g, 7.6 mmol), 3-amino-5-methylpyrazol (1.5 g, 15.44 mmol), acetic acid (10 ml) were sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 1.5 ml MeOH, and this solution was added dropwise to 30 ml water. After stirred for 1 hour, the solid was collected and was purified by flash column chromatography to give product (2.2 g, 85%). LC-MS: m/e 342 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:42])[CH2:3][C:4]([CH3:41])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:20]=[CH:21][C:14]=23)[CH:8]=1)[CH2:5][CH3:6].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[C:15]2=[N:16][CH:17]=[CH:18][C:13]([C:9]3[CH:8]=[C:7]([C:4]([CH3:41])([CH2:5][CH3:6])[CH2:3][N:2]([CH3:1])[CH3:42])[CH:12]=[CH:11][CH:10]=3)=[C:14]2[CH:21]=[N:20]1
Reactant: CCC(C)(CN(C)C)c1cccc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(CN(C)C)c1cccc(-c2ccnc3[nH]ncc23)c1
Yield: 24.6 %

Procedure:
N,N,2-trimethyl-2-(3-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)butan-1-amine (89.3 mg, 0.1621 mmol) was dissolved in dry DCM (2 mL) and cooled in an ice-bath. Triethylsilane (75.39 mg, 103.6 μL, 0.6484 mmol) was added followed by TFA (2 mL). The resultant mixture was stirred at 0° C. for 85 minutes and then concentrated under vacuo. The residue was partitioned between EtOAc and 1:1 c.HCl/water. The organic layer was extracted further with 1:1 c.HCl/water (3×20 mL) and the combined aqueous material was cooled in an ice-bath and carefully basified with 5M NaOH. The basic aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organics were washed with brine (3×10 mL), dried over Na2SO4, filtered and concentrated under vacuo to give a yellow gum. This was purified by column chromatography (10% MeOH in DCM, ˜75 mL silica) to give a colourless gum which was triturated with pentane to give a white powder (12.3 mg, 24% Yield).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH2:8]OC.[OH-].[Na+]>>[CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH:7]=[CH2:8]
Reactant: COCCC(=O)NCCN(C)C
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCCN(C)C

Procedure:
174.2 g (1.0 mole) of N-(2-dimethylaminoethyl)-3-methoxypropionamide (according to Example 17) are heated with 1.5 g of sodium hydroxide in a high vacuum at 90° to 110° C. Within about 30 minutes the methanol is split off, vigorous foaming occurring. The temperature is increased and 85 g (0.6 mole=60% of the theoretical yield) of colorless oil having a Bp0.1 of 85°-90° C. are distilled off.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3]>CO.[Pd]>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)NCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)NCC(=O)OC

Procedure:
2.0 g of Z-Ala-Ile-Gly-OMe are dissolved in 40 ml of methanol with gentle warming and then hydrogenated in the presence of 300 mg of Pd on charcoal (10 %). After completion of the hydrogenation the catalyst is filtered off and the filtrate completely evaporated to dryness. The residue, which is homogeneous in a thin layer chromatogram, is immediately processed further.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:4]=[N:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1.[CH3:18][C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][NH:20]1>>[ClH:2].[ClH:1].[ClH:2].[CH:15]([N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[N:5]=[N:4][C:3]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=3)=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCC(c2ccc(Cl)nn2)CC1
Reactant: CC1(B(O)O)C=CC=CN1
Agent: Cl
Product: Cc1cc(-c2ccc(C3CCN(C(C)C)CC3)nn2)ccn1

Procedure:
3-Chloro-6-(1-isopropylpiperidin-4-yl)pyridazine, hydrochloride (0.5 g, 1.6 mmol) and 2-methylpyridin boronic acid (0.241 g, 1.76 mmol) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as white crystals of the trihydrochloride. Yield: 164 mg (25%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH:12]3[CH2:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:25]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH:12]3[CH2:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1)[CH3:26]
Reactant: COC(=O)c1cc(O)c2cccc(C3CC3)c2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2c(C3CC3)cccc12
Reaction time: 12 h

Procedure:
To a stirred solution of 1.04 g (4.28 mmol) of methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate in 11 mL of DMF was added 1.18 g of K2CO3 and 0.68 mL of ethyl iodide successively and the mixture was stirred at 60 deg C. for 12 hr. The mixture was partitioned between AcOEt and H2O and the organic layer was washed with H2O and satd. brine, dried over anhydrous Na2SO4, and then concentrated. The residue was purified on SiO2 column chromatography (eluted with n-Hex/AcOEt=19/1) to yield methyl 4-ethoxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](=[CH:28]/[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](=[CH:28]/[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCC/C=C(\C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC/C=C(\C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
700 mg (1.47 mmol) of methyl (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido]benzoate, 25 ml of methanol and 1.2 ml (14.7 mmol) of a 35% sodium hydroxide solution were introduced into a round-bottomed flask. The mixture was stirred at room temperature for 12 hours, the reaction medium was poured into water, acidified to pH 1 with hydrochloric acid (37%), extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in heptane, filtered and dried. 555 mg (82%) of (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido]benzoic acid of melting point 183°-4° C. were recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1O.CC1CCCC(C(C)(C)C)C1=O.[NH3:25].C1(=O)CCCCC1>[Pd].O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[NH2:25]
Reactant: N
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [Pd]
Agent: CC1CCCC(C(C)(C)C)C1=O
Solvent: O=C1CCCCC1
Solvent: O
Product: Cc1cccc(C(C)(C)C)c1N

Procedure:
In a pressure reaction vessel was placed 0.55 mole parts of 2-methyl-6-tert-butylphenol, 0.55 mole parts of 2-methyl-6-tert-butylcyclohexanone, 0.0045 mole parts of palladium (5 weight per cent on charcoal support) and 3 mole parts of ammonia. The vessel was sealed and, while stirring, heated to 250°C. (Water was not added in this example because the initial reaction of ammonia with cyclohexanone produced 0.55 mole part of water.) The mixture was stirred at this temperature for 3 hours and then cooled and distilled, giving a 46.8 per cent conversion to 2-methyl-6-tert-butyl aniline. The yield of 2-methyl-6-tert-butyl aniline based on consumed phenol was about 98 per cent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:35]1(B(O)O)[CH2:37][CH2:36]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([CH:35]5[CH2:37][CH2:36]5)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C5CC5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 88.9 %

Procedure:
A mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.38 mmol), cyclopropylboronic acid (166 mg, 1.93 mmol, 5.0 equiv), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol, 4 mol %) and K3PO4 (164 mg, 0.77 mmol, 2.0 equiv), in toluene (4.5 mL) was heated at the reflux temperature for 16 h with monitoring by UPLC-MS. The resulting mixture was heated at 90° C. for 1 h in a microwave apparatus, then concentrated under reduced pressure. The remaining material was treated with water (25 mL), and was then extracted with EtOAc (2×25 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material (205 mg) was was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 1 min., gradient to 90% CH2Cl2/10% MeOH over 10 min.; 90% CH2Cl2/10% MeOH for 4 min.) to give {1-[4-(7-cyclopropyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (162 mg, 87%):
Reaction SMILES: [O:1]([C:3](C)(C)C)[K].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC)=O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH:21]([CH:3]=[O:1])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)O[K]
Reactant: O=C(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: COC=O
Product: O=CC(Cc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Yield: 130.8 %

Procedure:
Into a 100 mL 3-neck round-bottom flask was weighed 0.336 g KO-t-Bu and 4 mL anhydrous THF was added. The mixture was cooled with an ice bath under nitrogen, and to it was added a solution of 0.29 g 1-(1-benzylpiperidin-4-yl)-3-phenyl-1-propanone from the last step and 1.80 g methyl formate in 12 mL THF over 5 minute with stirring. After stirring for an additional 15 min, the cooling bath was removed, and the yellowish cloudy mixture was stirred for 2 hours. The mixture was then poured into water, extracted with 4×50 mL ether, 40 mL dichloromethane, and 3×40 mL THF and the combined organic layers were washed with 50 mL each of water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.414 g of the title compound as a sticky yellowish solid. This crude product was used without further purification in the next step. RF: 0.59 (EtOAc with 3% (v/v) Et3N and 5% (v/v) MeOH). 1H NMR (500 MHz, DMSO-d6): δ7.97 (s, 1H), 7.20˜7.30 (m, 5H), 7.14˜7.17 (m, 2H), 7.04˜7.09 (m, 3H), 6.85 (s, 1H), 3.45 (s, ˜2H), 2.81˜2.89 (m, 1H), 2.76˜2.80 (m, 2H), 1.97˜2.03 (m, 2H), 1.46˜1.56 (m, 4H). The Ph—CH2—C═ signal was not observed, possibly overlapping with the large water signal. ESI-MS 336.1 (M+H), HPLC A: 2.32 min.