Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:37])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([Se:24][C:25]#[C:26][C:27]3[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[CH:29][CH:28]=3)[CH:15]=[CH:14][C:13]1=2.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:37])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16]([Se:24][C:25]#[C:26][C:27]3[CH:36]=[CH:35][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(CO)cc3)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A 1 M solution of diisobutylaluminium hydride in toluene (4 ml, 4 mmol) is added dropwise, at 0° C., to a solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate obtained according to Example 4 (750 mg, 1.8 mmol), in toluene (20 ml). The solution is stirred for 4 h at 0° C. and is then treated with a double potassium sodium tartrate solution, filtered and taken up in a mixture of ethyl ether and water. The organic phase is washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. 418 mg (60%) of a colourless oil are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21]CC)=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CCO.O>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([OH:21])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of ethyl 2-(4-(benzyloxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.24 mmol) in EtOH (5 mL) was added an aqueous solution of lithium hydroxide (20.1 mg, 0.48 mmol) in water (1 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1 N HCl to pH=3. The resulting mixture was extracted with EtOAc (15 mL) and combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (17 mg, yield: 18%). 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.44-7.34 (m, 5H), 7.06 (d, J=19.2 Hz, 2H), 5.50 (d, J=8.8 Hz, 1H), 5.172 (m, 5H), 3.2 (d, J=15.6 Hz, 1H), 2.18-2.11 (m, 1H). MS (ESI) m/z=393 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19]C)[CH:18]=1)[CH2:6][CH2:5]2>Br>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([OH:19])[CH:18]=1)[CH2:6][CH2:5]2
Reactant: COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: Br
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
6-Chloro-2-(5-methoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (1.44 g, 5 mmol, example 10) was dissolved in aq. HBr (48%, 20 mL). The reaction mixture was heated to reflux temperature and stirred overnight. After cooling to room temperature, it was carefully neutralized with satd. aq. NaHCO3 solution and extracted with EtOAc (2×25 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (1.02 g, 74%) as brown oil. MS: 275.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25].N1C=CC=CC=1>C1COCC1>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:24]#[N:25])[CH:27]=2)=[O:34])=[C:3]([F:23])[CH:4]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(C#N)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.2 %

Procedure:
A suspension of Example A3 (0.250 g, 0.710 mmol) in THF (10 mL) was treated with 3-cyanophenyl isocyanate (0.102 g, 0.710 mmol) followed by pyridine (0.011 g, 0.142 mmol) and stirred at RT for 2 days. The mixture was concentrated to dryness and the residue treated with MeCN. The solid was collected via filtration, treated with MeOH and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (212 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.89 (s, 1H), 8.79 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.97 (t, J=1.8 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=10.6 Hz, 2H), 7.44 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 496.1 [M+H]+.
Reaction SMILES: [C:1]([Li])(C)([CH3:3])[CH3:2].CCCCC.CC1C=C(C)C=C(C)C=1Br.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][N:30]=[C:29]1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[CH3:42])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(Br)C=C>C1COCC1.O.CCOC(C)=O.C(O)(=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][N:30]=[C:29]1[CH:33]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[CH3:42])[CH2:3][CH:1]=[CH2:2])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: [Li]C(C)(C)C
Reactant: Cc1cccc(OCC2=NCCN2C(=O)OC(C)(C)C)c1C
Agent: Cc1cc(C)c(Br)c(C)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(Oc1cccc(C)c1C)C1=NCCN1C(=O)OC(C)(C)C
Temperature: -20 °C

Procedure:
A solution of t-butyllithium in pentane (1.7M, 5.7 ml, 9.84 mmol) was added in portions to a solution of 2,4,6-trimethylphenylbromide (0.744 ml, 980 mg, 4.93 mmol) in 8 ml THF at ca −78° C. A white precipitate was formed. After 10 minutes at low temperature a solution of 2-(2,3-dimethyl-phenoxymethyl)-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (1 g, 3.28 mmol) in 6 ml THF was added in portions to give an orange solution. This was warmed to −20° C. and cooled again to ca −70° C. whereupon much of the solid went into solution. Allyl bromide (0.332 ml, 475 mg, 3.93 mmol) was added and the reaction mixture stirred for 30 min at this temperature before a small amount of acetic acid was added. The mixture was warmed and shaken between EtOAc and water. The organic phase was dried with Na2SO4 and evaporated to give 1.3 g of crude product, which was chromatographed on silica to yield 2-[1-(2,3-dimethyl-phenoxy)-but-3-enyl]-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester. 1H-NMR (CDCl3) (selection) 5.10 (d, allyl), 5.18 (d, allyl), 5.66 (t, OCH), 5.98 (m, allyl)
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[C:48]1[CH2:67][C:59]3([CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61][CH2:60]3)[CH2:58][C:49]1=[C:50]2[C:55](=[O:57])[CH3:56].CCCCCC.CCOC(C)=O.[CH3:80][NH:81][CH3:82]>C1COCC1>[CH3:80][N:81]([CH3:82])[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[C:48]1[CH2:67][C:59]3([CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61][CH2:60]3)[CH2:58][C:49]1=[C:50]2[C:55](=[O:57])[CH3:56]
Reactant: CC(=O)c1c2c(cc3c(Cl)cccc13)CC1(COC(C)(C)OC1)C2
Reactant: CNC
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1c2c(cc3c(N(C)C)cccc13)CC1(COC(C)(C)OC1)C2
Yield: 62 %

Procedure:
Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0015 g, 0.0021 mmol), LHMDS (0.17 mL of a 1.0 M solution in THF, 0.17 mmol), 5a (0.030 g, 0.087 mmol) in THF (0.3 mL), dimethylamine (0.065 mL of a 2.0 M solution in THF, 0.13 mmol). The title compound was isolated (n-hexane/AcOEt 8:2, 0.019 g, 62% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH:9]1[C:22]2[CH:21]([C:23](Cl)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:23]([CH:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][C:13]3[C:22]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:24])=[N:6]1)[CH3:8]
Reactant: CCn1nnc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Cc2ccccc21
Product: CCn1nnc(NC(=O)C2c3ccccc3Cc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 206-207° and MS: (neg. ions): m/e=318.3 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and 9,10-dihydro-anthracene-9-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.O=P(Cl)(Cl)[Cl:23].C(N(CC)C(C)C)(C)C>C(Cl)CCl>[Cl:23][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one (0.60 g, 2.17 mmol), POCl3 (0.5 mL), and N,N-diisopropylethylamine (1.5 mL) in ClCH2CH2Cl (6 mL) was heated at 100° C. for 4 hours. After the solvent and reagents were evaporated under reduced pressure, toluene was added to the residue, and the solution was evaporated under reduced pressure. The residue was dried under vacuum to afford 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline as a brown solid. LC-MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][NH2:11])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CS[C:19](=N)[NH2:20].OS(O)(=O)=O>>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[NH2:20][C:19]1[NH:11][CH2:10][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]=1
Reactant: NCC(CN)c1ccccc1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Product: NC1=NCC(c2ccccc2)CN1
Temperature: 265 °C
Reaction time: 0.08 h
Yield: 51.3 %

Procedure:
A stirred mixture consisting of 3.25 g of 2-phenyl-1,3-propanediamine (prepared in accordance with Preparation C) and 3.02 g of 2-methyl-2-thiopseudourea sulfate ([CH3SC(NH)NH2 ]2.H2SO4) in a small flask is immersed in a 245° C. oil bath. The temperature is raised to 265° C. when the reaction mixture solidifies. When the reaction mixture melts again, it is stirred for about five minutes then is removed from the oil-bath. The contents are refluxed with 50 ml of methanol until a powder is formed. The mixture is cooled and the solid product is collected on a Buchner-funnel, washed with 30% ether in methanol and is air-dried to give 3.7 g of crude product. Recrystallization from 20 ml of water yields 2.25 g of 2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine sulfate, mp 264°-267° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].S(Cl)([Cl:21])=O>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:21])=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=S(Cl)Cl
Reactant: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To 1.2 g (4.5 mmole) of (-)-2-(4-fluoro-3-trifluoromethylphenoxy)butanoic acid dissolved in 15 ml methylene chloride was added one drop of pyridine and further added dropwise 0.6 g of thionyl chloride. The reaction mixture was further stirred at room temperature for 4 hours and then thionyl chloride and methylene chloride were removed under reduced pressure to obtain 1.2 g of (-)-2-(4-fluoro3-trifluoromethylphenoxy)butanoic acid chloride. The resulting mixture was applied for the next reaction without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](O)[C:9]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].S(Cl)([Cl:26])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:26])[C:9]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(O)c2ccc(-c3ncccc3C)nc2n1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2ccc(-c3ncccc3C)nc2n1
Temperature: 25 °C

Procedure:
Dissolve 4-hydroxy-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-2-carboxylic acid ethyl ester (345 mg, 1.11 mmol) in thionyl chloride (15 mL) and heat the mixture at reflux overnight. Cool the mixture to room temperature and remove the excess thionyl chloride in vacuo. Dissolve the crude reaction mixture in CH2Cl2 (50 mL) and wash with saturated NaHCO3 (aq). Dry the organic layer over Na2SO4 and remove the solvent under reduced pressure to yield the title compound. MS 329.12 (M+1)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O>[Zn].C(O)(=O)C>[NH2:12][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH2:9][CH2:10][OH:11])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(SCCO)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a suspension of 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol (323 mg, 1.5 mmol) and 7 ml of acetic acid, zinc dust (220 mg, 3.4 mmol) was added at 0° C. The mixture was stirred at room temperature for 2 hr. Zinc dust was filtered through celite and the residue was purified by HPLC to provide 2-(5-amino-6-methyl-pyridin-2-ylsulfanyl)-ethanol as an oil (93 mg, 33%). 1HNMR (DMSO-d4, 400 MHz) δ 1.91 (s, 1H), 2.38 (s, 3H), 2.50-2.51 (m, 2H), 3.12-3.15 (m, 2H), 3.57-3.61 (m, 2H), 7.26-7.28 (m, 1H), 734-7.36 (m, 1H). Exact mass calculated for C8H12N2OS 184.07 found 184.9 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19](CC2SC=C(C(OC)=O)N=2)[CH2:18][CH2:17]1)=[O:13].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:37][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:33][C:34]2[N:35]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:37][CH:38]=2)[CH2:18][CH2:17]1)=[O:13]
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Reactant: CCOC(=O)c1nc(CCl)cs1
Product: CCOC(=O)c1nc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)cs1

Procedure:
Ethyl 4-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}-1,3-thiazole-2-carboxylate 13 was prepared, according to the procedure described for compound 7, using ethyl 4-(chloromethyl)-1,3-thiazole-2-carboxylate. Yield: 45 mg, 11%.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[N:25]2>>[F:18][C:15]([F:16])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:14]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Reactant: COc1ccc2c(N)cccc2n1
Product: COc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 13, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 122 mg of 5-amino-2-methoxyquinoline are converted into 190 mg of product.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH2:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-:14].[Na+]>CC(C)=O>[CH3:1][Si:2]([CH3:13])([CH2:9][CH2:10][CH2:11][I:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: C[Si](C)(CCCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(CCCI)c1ccccc1

Procedure:
Dimethyl(3-chloropropyl)phenylsilane [J. W. Wilt, W. K. Chwang, C. F. Dockus and N. M. Tomiuk, J. Am. Chem. Soc., 100, 5534, (1978)] (9 g, 48.8 mmol) and sodium iodide (29.5 g, 195 mmol) are refluxed in acetone during 24 hours. The mixture is filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in diethyl ether and washed with water. The organic layer is dried with sodium sulfate, filtered and concentrated under reduced pressure to afford pure dimethyl(3-iodopropyl)phenylsilane as a slightly yellow oil (12.5 g, 93%).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[N:7][C:6]=1[NH:13][CH3:14])C.[OH-].[K+].[C:18]([C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[C:18]([C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:4](=[O:15])[C:5]2[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[N:7][C:6]=2[NH:13][CH3:14])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: CCOC(=O)c1cc(CC)cnc1NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCc1cnc(NC)c(C(=O)N(CCc2ccc(Cl)c(Cl)c2)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A mixture of 5-ethyl-2-methylamino-nicotinic acid ethyl ester (40 mg, 0.19 mmol), 2 M aq. potassium hydroxide solution (0.19 mL, 0.38 mmol) and THF was heated at 60° C. for 16 h, then evaporated to dryness. The residue was taken up in DMF (3.2 mL) and treated with (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (71 mg, 0.21 mmol), HBTU (109 mg, 0.29 mmol), and 4-methylmorpholine (58 mg, 0.57 mmol). The homogeneous solution was stirred at RT for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced the title compound (77 mg, 80%). Light yellow oil, MS (ISP) 498.4 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:27])[CH3:26]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg) and acetic anhydride (100 mg) in dry pyridine (2 ml) was stirred at 90° C. for one hour. The cooled mixture was poured into an ice water (10 ml). The precipitated solid was collected, washed with water, and dried under reduced pressure to give 8-(3-acetylamino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (65 mg) as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:15]=[N:16][CH:17]=1)[CH:22]=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Yield: 29.7 %

Procedure:
3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromopyridine (0.95 g, 2.77 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine) palladium (100 mg) and allyltributyltin (1.72 mL, 5.54 mmol). The mixture was stirred and refluxed for two days. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (250 mg, 30%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.37 (d, 2H, J=7.0 Hz), 3.87-3.92 (m, 2H), 4.16 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 5.07-5.17 (m, 2H), 5.9 (m, 1H), 7.07 (m, 1H), 8.08 (m, 1H), 8.19 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 305 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH:13]=2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CCO.N#N>[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(C2=CCC3(CC2)OCCO3)ccc1N
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CNC(=O)c1cc(C2CCC3(CC2)OCCO3)ccc1N
Reaction time: 8 h

Procedure:
10% Pd—C (50% H2O w/w) (264 mg, 0.124 mmol) was added to a solution of 2-amino-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-methylbenzamide (Compound 139C, 357 mg, 1.24 mmol) in EtOH (30 mL, 500 mmol). The reaction mixture was subjected to three cycles of evacuation and N2 purging. After a fourth evacuation, the mixture was flushed with H2 and allowed to stirred under hydrogen overnight. The catalyst was removed by filtration through a pad of celite, and the filtrate was evaporated under reduced pressure to give the title compound as 333 mg of a pinkish solid. 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.78 (m, 8H), 2.34-2.44 (m, 1H), 2.71 (d, J=4.55 Hz, 3H), 3.88 (t, J=2.40 Hz, 4H), 6.20 (s, 2H), 6.60 (d, J=8.34 Hz, 1H), 6.98 (dd, J=8.46, 1.89 Hz, 1H), 7.29 (d, J=2.02 Hz, 1H), 8.16 (d, J=4.55 Hz, 1H). MS (ES+): m/z=291.08 (100) [M+1]. HPLC: tR=2.60 min (ZQ3, polar—5 min).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:17][C:18](=[O:20])[CH3:19])[CH2:14][CH2:15][CH3:16].[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C:23](=[O:29])[CH2:22]2>O1CCCC1.O>[CH2:13]([O:17][C:18](=[O:20])[CH2:19][C:23]1([OH:29])[CH:24]2[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]2)[CH2:22]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(C)=O
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCCCOC(=O)CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a 0° C. solution of diisopropylamine (6.7 ml) in tetrahydrofuran (THF) (20 ml) was added 2.3M nBuLi (20 ml). The reaction mixture was stirred for 40 minutes and then cooled to -78° C. To this mixture was added dropwise a solution of 1 butylacetate (6.4 ml) in 10 ml of THF and stirring continued for an additional 15 minutes. Quinuclidin-3-one (free base) (5.0 g) in THF (15 ml) was added to the mixture dropwise and the mixture was allowed to warm to 0° C. over 1 hour. To this solution was added water (100 ml), the solution was extracted twice with chloroform and the combined extracts were washed once with brine. The resulting solution was dried over MgSO4, filtered and dried in vacuo to give 9.53 g of the subtitle compound as an off-white solid.