Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])=[O:36])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]([O:11][CH:12]([N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][CH:18]=[N:17][C:16]1=2)[CH:13]=[O:14])[CH2:4][P:5]([O:9][Na:10])([O:7][Na:8])=[O:6])=[O:2].[NH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O>[OH:14][CH:13]1[C@H:12]([N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:24])[NH:19][CH:18]=[N:17][C:16]2=3)[O:11][C@@H:3]([CH2:4][P:5]([O:9][Na:10])([O:7][Na:8])=[O:6])[CH:1]([OH:2])[N:25]1[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=CC(CP(=O)(O[Na])O[Na])OC(C=O)n1cnc2c(=O)[nH]cnc21
Reactant: Nc1ncccn1
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@@H](CP(=O)(O[Na])O[Na])C(O)N(c2ncccn2)C1O
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 88.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-disodiophosphonoethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (1.95 g) was dissolved in water (50 ml). To the solution was added 2-aminopyrimidine (0.48 g). The solution was stirred at ambient temperature for 1.3 hours and evaporated in vacuo. The residue was triturated with acetone and dried over phosphorus pentoxide in vacuo to give 9-[(2R, 6R)-3,5-dihydroxy-6-disodiophosphonomethyl-4-(pyrimidin-2-yl)morpholin-2-yl]hypoxanthine (2.1 g).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[C:32]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[C:33]([CH:41]=[CH:42][CH:43]=2)[O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:14]=1.[F:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[C:46]([CH2:45][CH2:44][C:32]1[C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[CH:14]=[C:9]([C:54]3[CH:53]=[CH:52][CH:51]=[C:50]([F:49])[CH:55]=3)[CH:10]=2)=[CH:43][CH:42]=[CH:41][C:33]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])([OH:48])=[O:47]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(C)c1ccc(-c2cc(Br)cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)c2)cc1
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
Solvent: O
Product: CN(C)c1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3cccc(F)c3)c2)cc1
Temperature: 90 °C

Procedure:
In a reaction vessel charged with 4 mL of toluene and 1 mL of water, was added 45 mg (0.072 mmol) of 4-[3-[6-(5-bromo-4′-dimethylamino-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid, 3-fluorophenylboronic acid (20 mg, 0.144 mmol), and potassium phosphate (35.9 mg, 0.144 mmol). This mixture was put under an atmosphere of nitrogen and 4.16 mg of tetrakis(triphenylphosphine)palladium(0) was added. This mixture was stirred and was heated overnight at 90° C. At this time, analysis of an aliquot by LC-MS, indicated the formation of the desired product. To the reaction mixture was added 2N HCl to effect pH=˜6. The aqueous phase was thrice extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to provide a solid which was purified by preparative HPLC to provide 46 mg of product. Example 57 was characterized by low resolution mass spectrometry where signals corresponding to the following were observed: ES(+)=598+Na, ES(−)=597. Example 57 was also characterized by high resolution mass spectrometry where signals corresponding to the following were observed: m/e calculated for C37H39FO6 598.273068; found compatible with (M+Na)1+=621.2624.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:48])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:49][CH3:50])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:51](C1C=C(C(C)C)C=C(C(C)C)C=1S(NN)(=O)=O)(C)C.C(N(CC)CC)C>CO>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:48])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:51])[C:13]([O:49][CH3:50])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Yield: 6 %

Procedure:
To a solution of olefin N-[17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)-sulfonamide (63, 100 mg, 0.139 mmole) in MeOH (3.0 mL) heated at 80° C., was added 2,4,6-triisopropylbenzene sulfonohydrazide (TrisNHNH2) and triethylamine portion wise over several hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and a saturated solution of NaHCO3, successively washed with HCl 1N and brine, dried (MgSO4), filtered and evaporated. Purification by flash chromatography (gradient of AcOEt/CH2Cl2, 0:1 to 1:9) followed by recrystallization from isopropylether/petroleum ether, and then preparative HPLC afforded 6 mg (6%) of the title product (59) as a white powder: m/z=724 (M+H)+. 1H NMR (CDCl3): 0.90-1.70 (m, 21H), 1.95-2.03 (m, 2H), 2.25-2.35 (m, 2H), 2.63-2.68 (m, 2H), 2.99 (m, 1H), 3.22 (m, 1H), 3.41 (m, 1H), 3.96 (m, 5H), 4.15 (d, J=15 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 5.53 (m, 1H), 6.57 (s, 1H), 7.05 (s, 1H), 7.12 (dd, J=2.5 Hz, 9.1 Hz, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.56 (s, 1H), 7.93 (d, J=9.1 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:8][O:9][CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:8][O:9][CH2:10][CH2:11][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccsc1Br
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Product: COCCc1sccc1C

Procedure:
This compound was prepared analogous to Example 61, starting with 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) and toluene-4-sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) The crude product was purified on silica gel with eluent n-heptane and tert.butylmethyl ether. The title compound was obtained as a light yellow oil, 490 mg. GC-MS (EI): M=156
Reaction SMILES: Cl.[NH2:2][NH2:3].[C:4]12[C:12](=[O:13])O[C:9](=[O:10])[C:5]=1[CH2:6][CH2:7][CH2:8]2>O>[C:9]1(=[O:10])[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:12](=[O:13])[NH:3][NH:2]1
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: NN
Agent: Cl
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of hydrazine hydrochloride (2.4 g, 22.8 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (3.0 g, 21.7 mmol) in water (10 mL) is heated to reflux for 3 h. The reaction mixture is cooled down to room temperature and the precipitate is collected by filtration. The yellow solid is mixed with 15 mL 1N NaOH and stirred for 2 h, filtered and dried under vacuum to give 2,3,6,7-tetrahydro-5H-cyclopenta[d]pyridazine-1,4-dione (38) (2.2 g, 67%).
Reaction SMILES: N[C:2]1[N:11]=[C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]([O:16][CH2:17][CH2:18][OH:19])=[C:14]([CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[C:4]([O:26][CH3:27])=[CH:5][C:6]([O:24][CH3:25])=[N:7]2.N([O-])=[O:29].[Na+]>O.Cl>[OH:19][CH2:18][CH2:17][O:16][C:15]1[C:20]([CH3:22])=[CH:21][C:12]([C:10]2[NH:11][C:2](=[O:29])[C:3]3[C:4]([O:26][CH3:27])=[CH:5][C:6]([O:24][CH3:25])=[N:7][C:8]=3[CH:9]=2)=[CH:13][C:14]=1[CH3:23]
Reactant: COc1cc(OC)c2c(N)nc(-c3cc(C)c(OCCO)c(C)c3)cc2n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)cc2n1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
2-[4-(5-amino-2,4-dimethoxy-[1,6]naphthyridin-7-yl)-2,6-dimethyl-phenoxyl]-ethanol (0.302 g, 0.82 mmol) in water (5 mL) and conc. Hydrochloric acid (3 mL) were mixed with stirring. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (0.305 g, 4.42 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 40 min. To the reaction mixture was added 1 N hydrochloric acid (10 mL) and heated at 55° C. for 50 min and then stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and the aqueous layer was basified with aqueous 5% NaOH and saturated NaHCO3 solution. Water was evaporated and the organic compound was washed with a dichloromethane/methanol solution and concentrated to leave a crude which was purified by silica gel (50 g) column chromatography, employing 50% ethyl acetate in hexane and hexane/ethyl acetate/methanol (3:2:1) as eluent, to obtain 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (0.080 g, 26%). Selected data: MS (ES) m/z: 371.1; MP 224.9-225.4° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH2:25][CH3:26])[C:16]=1[C:27]([OH:29])=O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:39]1([CH2:42][NH:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH2:41][CH2:40]1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C2C(=CC=CC=2)NC=1C(O)=O)C1N=NN(C)N=1.C(NCC)C>>[CH:39]1([CH2:42][N:43]([CH2:44][CH:45]2[CH2:47][CH2:46]2)[C:27]([C:16]2[N:17]([CH2:24][CH2:25][CH3:26])[C:18]3[C:23]([C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:3]([C:2]([F:38])([F:1])[F:37])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:29])[CH2:41][CH2:40]1
Reactant: C1CC1CNCC1CC1
Reactant: CCCn1c(C(=O)O)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc21
Agent: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)O)[nH]c3ccccc23)n1
Solvent: CCNCC
Product: CCCn1c(C(=O)N(CC2CC2)CC2CC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc21

Procedure:
3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-propyl-1H-indole-2-carboxylic acid (0.16 g, 0.29 mmol) and bis cyclopropylmethylamine (0.37 g, 0.29 mmol) were used to synthesize the title compound instead of using 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid and diethylamine in step (ii) of example 131 (0.08 g, 42%)
Reaction SMILES: ClN1C2C=CC=CC=2N=N1.N1C2C=CC=CC=2N=N1.[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][SH:29])([CH3:23])([CH3:22])[CH3:21].NC(N)=S.[CH3:35][C:36]([SH:39])([CH3:38])[CH3:37]>C(Cl)Cl.C1COCC1>[C:36]([S:39][S:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: CC(C)(C)S
Agent: Cln1nnc2ccccc21
Agent: NC(N)=S
Agent: c1ccc2[nH]nnc2c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCSSC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
1-Chloro-1H-benzo[d][1,2,3]triazole (1.73 g, 11.28 mmol) and 1H-benzo[d][1,2,3]triazole (0.67 g, 5.64 mmol) were dissolved in DCM (24.0 ml) under a nitrogen atmosphere, the mixture was cooled to −78° C., and a solution of tert-butyl(2-mercaptoethyl)carbamate (Compound 6a) (1.00 g, 5.64 mmol) in DCM (3.0 ml) was added dropwise. Following stirring at 78° C. for 10 minutes, a suspension of thiourea (1.29 g, 16.92 mmol) in THF (6.0 ml) was added and the mixture was further stirred for 10 minutes. A solution of 2-methylpropane-2-thiol (0.76 g, 8.46 mmol) in DCM (3.0 ml) was then added dropwise, and the mixture was stirred with warming to room temperature for 20 hours. The solid in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1) to afford the title compound (1.15 g, 77%).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([CH:56]=[CH:57][C:58]=2[F:59])[NH2:55])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([NH:55][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:56]=[CH:57][C:58]=2[F:59])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.357 mL, 2.64 mmol) the title compound of Step A was obtained as a light yellow solid (857 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 7.64-7.72 (m, 1H), 7.49-7.56 (m, 1H), 7.21-7.32 (m, 3H), 6.55 (d, J=5.3 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[Br:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(C)OC)=[O:22])=[CH:19][CH:18]=1.O>C1COCC1>[Br:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([C:6]2[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([F:1])[CH:7]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2-fluoro-4-bromoanisole (3.03 g, 14.8 mmol) in anhydrous THF (100 mL) was added n-butyllithium (1.6 M in hexanes, 10.2 mL, 16.3 mol) dropwise at −78° C. The reaction mixture was stirred for 1 h and 80 (4.02 g, 16.3 mmol) dissolved in THF (20 mL) was added dropwise. The reaction mixture was warmed to −20° C. over 1 h, water (100 mL) was added, and the volatiles were removed under reduced pressure. The mixture was extracted with ether (3×100 mL) and the combined extracts were washed with water (100 mL) and brine (100 mL). The mixture was dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (20:1 to 5:1 hexanes:EtOAc) to afford 2.35 g (51%) of 81 as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3H), 7.01 (t, J=8.4 Hz, 1H), 7.55-7.62 (m, 6H).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=O.C(OP([CH2:56][C:57]#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[CH:56][C:57]#[N:58])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4'-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'nitrobenzophenone (4 g, 14 mmol), diethylcyanomethylphosphonate (2.5 mL, 15.4 mmol) and lithium hexamethyldisilazide (11.8 mL, 15.4 mmol, 1.3M) with a reaction time of 17 hours at room temperature. The crude product was purified by chromatography (silica gel, 3% hexane/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120° C.; 1H NMR (CDCl3) δ 8.40-8.20 (m, 4 H), 7.70-7.46 (m, 4 H), 7.06-6.75 (m, 6 H), 5.84 (s, 1 H), 5.70 (s, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H); 13C NMR (CDCl3) δ 160.3, 151.7, 151.1, 149.2, 148.9, 148.7, 148.5, 148.5, 143.5, 130.6, 129.9, 129.6, 128.2, 123.7, 123.1, 122.2, 117.4, 117.3, 112.3, 111.0, 110.5, 96.2, 94.9, 56.0, 56.0; Anal. Calcd for C17H14N2O4. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.45; H, 4.66; N, 8.82.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19](=[O:27])[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:19](=[O:27])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:22][CH2:23]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1nc(OCC(=O)NC2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)NC2CCN(C(=O)c3ccc(F)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 57 and 4-fluorobenzoyl chloride in the same manner as in Example 32.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:22](Cl)[O:23][CH3:24]>CC(C)=O.CCOC(C)=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COCOc1ccccc1C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a stirring solution of 2-hydroxybenzophenone (3.0 g, 15.1 mmol) and K2CO3 (9.94 g, 71.9 mmol) in acetone (80 mL) under reflux was added MOMCl (2.9 mL, 37.8 mmol) and allowed to stir overnight. The reaction was then cooled to 23° C., diluted with EtOAc, washed with 2N NaOH (3×), the organic phase dried (Na2SO4), filtered and concentrated to provide the product (605 mg) as an oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67-7.72 (2H, m), 7.63 (1H, d, J=7.07 Hz), 7.48-7.54 (3H, m), 7.34 (1H, dd, J=7.33, 1.52 Hz), 7.24 (1H, d, J=8.34 Hz), 7.13 (1H, t, J=7.45 Hz), 5.08 (2H, s), 3.13 (3H, s).
Reaction SMILES: C([Mg]Br)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[C:14]/[CH:15]=[CH:16]\C#C.[Si]([O:26]C1C=NC2C(C=1)=CC(OC)=CC=2)(C(C)(C)C)(C)C.ClC(OC12CC3CC(CC(C3)C1)C2)=O>C1COCC1.C(OCC)C>[O:26]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: COc1ccc2ncc(O[Si](C)(C)C(C)(C)C)cc2c1
Reactant: C#C/C=C\C#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: O=C(Cl)OC12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of ethylmagnesium bromide in THF (43 ml 1M solution, 43.3 mmol) was added to a solution of z-hept-4-ene-2,6-diyn-1-ol tetrahydropyranyl ether 18 (6.89 g, 36.2 mmol) and 6-methoxy-3-(tert-butyldimethylsiloxy)-quinoline 17 (9.41 g, 32.5 mmol) in THF (210 ml) cooled to 0° C. After the initial evolution of gas the reaction mixture was stirred for 20 minutes at 0° C. and a solution of adamantyl chloroformate (11.51 g, 53.6 mmol) in THF (40 ml) was added via syringe pump over 90 minutes while maintaining the temperature at 0° C. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours before quenching with saturated aqueous sodium bicarbonate solution (60 ml). The resulting mixture was extracted with ether (1×300 ml, 2×150 ml), the combined organic extracts dried over magnesium sulphate and evaporated to give a brown oil. Flash column chromatography on silica gel eluting with 80% pentant, 20% diethylether yielded 16.11 g, (75%) of the desired product 19 as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ7.43 (s, 1H), 6.62 (dd, J=8.8, 2.8 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H), 5.74 (dd, J=11.0, 1.4 Hz, 1H), 5.68-5.79 (s, 1H), 5.67 (d, J=11.0 Hz, 1H 5.62 (s, 1H), 4.75 (s, 1H), 4.31 (dd, J=16.0, 1.4 Hz, 1H), 4.23 (dd, J=16.0, 1.4 Hz, 1H), 3.77-3.89 (m, 1H), 3.76 (s, 3H), 3.46-3.58 (m, 1H), 2.15 (s, 9H), 1.64 (s, 6H), 1.45-1.89 (m, 6H), 0.96 (s, 9H), 0.25 (s, 3H), 0.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ156.3 (e), 152.0 (e), 128.9 (c), 125.5 (o), 124.8 (e), 119.5 (o), 119.3 (o), 110.5 (o), 109.9 (o), 103.5 (o), 96.8 (o), 93.1 (e), 92.8 (e), 82.7 (e), 81.6 (e), 80.1 (e), 61.9 (e), 55.3 (o), 54.7 (e), 48.8 (o), 41.5 (e), 36.1 (e), 30.9 (o), 30.2 (e), 25.5 (o), 25.3 (e), 1.9.0 (e), 18.1 (e), -4.3 (o), -4.7 (o); IR (CHCl3) 1687 cm-1; MS (FAB) m/e calculated for C39H51NO6Si: 657.349 , found 657.351.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([CH3:29])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([CH3:29])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(OCc3ccccc3)cccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(O)cccn12
Yield: 63.6 %

Procedure:
A solution of 5-(8-benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.6 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (wet, 0.5 g) under an atmospheric pressure of hydrogen at ambient temperature for an hour. The catalyst and an insoluble material were filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of tetrahydrofuran and ethanol to give 5-(8-hydroxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (0.78 g). mp. >280° C.