Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:24]=4)[O:20][C:19]3=[O:40])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N1C2C(=CC=CC=2)C(C2C=C(C3C4C(=CC=CC=4)N(CC)C=3C)OC2=O)=C1C)C.[CH3:71][O:72][C:73]1[CH:74]=[C:75]2[C:79](=[CH:80][C:81]=1[O:82][CH3:83])[NH:78][CH:77]=[CH:76]2.C(N1C2C(=CC=CC=2)C=C1C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[C:19](=[O:40])[O:20][C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:24]=4)([C:76]4[C:75]5[C:79](=[CH:80][C:81]([O:82][CH3:83])=[C:73]([O:72][CH3:71])[CH:74]=5)[NH:78][CH:77]=4)[CH:22]=3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC(c2cn(Cc3ccccc3)c3cc(F)ccc23)=CC1c1cn(Cc2ccccc2)c2cc(F)ccc12
Reactant: COc1cc2cc[nH]c2cc1OC
Agent: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Agent: CCn1c(C)cc2ccccc21
Product: COc1cc2[nH]cc(C3(c4cn(Cc5ccccc5)c5cc(F)ccc45)C=C(c4cn(Cc5ccccc5)c5cc(F)ccc45)C(=O)O3)c2cc1OC

Procedure:
When 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-2(3H)-furanone is substituted for 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone and 5,6-dimethoxyindole is substituted for 1-ethyl-2-methylindole in the procedure described in part C of this example, there is obtained 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-5-(5,6-dimethoxy-3-indolyl)-2(5H)-furanone (Formula III: R=C6H5CH2 ; R1 =R2 =R3 =H; Y=6-F; Y1 =5,6-(CH3O)2).
Reaction SMILES: [Na].Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)C>[NH2:15][C:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[N:11]=1
Reactant: Cc1ccc(NN)cc1
Reactant: C=CC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(N2CCC(N)=N2)cc1
Reaction time: 0.08 h

Procedure:
A 2.8 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 15.86 g. of p-methylphenylhydrazine hydrochloride is added followed in 5 minutes by 5.5 g. of acrylonitrile. The reaction mixture is refluxed for 18 hours, then is evaporated to dryness in vacuo. Water is added and the separated solid is collected by filtration. The solid is dissolved in dichloromethane and passed through a short column of a hydrous magnesium silicate. The effluent is refluxed with the gradual addition of hexane to separate a crystalline product. The entire crystallization step is repeated to give 3.4 g. of the product of the Example as colorless plates, m.p. 142°-143° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:23])[CH2:14][C:13]2[C:15]([CH3:22])=[C:16](Br)[C:17]([CH3:20])=[C:18]([CH3:19])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[CH2:1]([O:8][CH2:9][C:10]1([CH3:23])[CH2:14][C:13]2[C:15]([CH3:22])=[C:16]([N:35]3[CH2:34][CH2:33][N:32]([C:29]4[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=4)[CH2:37][CH2:36]3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(COCc1ccccc1)O2
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COCc3ccccc3)O4)CC2)cc1
Yield: 64.8 %

Procedure:
By using 2-[(benzyloxy)methyl]-5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (690 mg, 1.84 mmol) synthesized in Reference Example 159 and 1-(4-methoxyphenyl)piperazine (707 mg, 3.68 mmol), the reaction was carried out in the same manner as Example 1 to synthesize 580 mg of the title compound (yield 65%). An oily product.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:13])=[N:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][CH:12]=1.[CH3:14][S:15][C:16]1[N:21]=[C:20]([Sn](C)(C)C)[CH:19]=[CH:18][N:17]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:7]1[N:6]=[C:5]([NH2:13])[CH:4]=[N:3][C:2]=1[C:18]1[CH:19]=[CH:20][N:21]=[C:16]([S:15][CH3:14])[N:17]=1
Reactant: CSc1nccc([Sn](C)(C)C)n1
Reactant: Nc1cnc(Br)c(-c2ccco2)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nccc(-c2ncc(N)nc2-c2ccco2)n1
Temperature: 150 °C
Yield: 47 %

Procedure:
A microwave oven reactor was charged with 5-bromo-6-furan-2-ylpyrazin-2-ylamine (Preparation 2, 220 mg, 0.91 mmol), 2-methylsulfanyl-4-trimethylstannanylpyrimidine* (500 mg, 1.74 mmol), bis-(triphenylphosphin)palladium (II) chloride (60 mg, 0.08 mmol) and dimethylformamide (2.5 mL). The mixture was heated at 150° C. for 10 min in the microwave oven, then cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (dichloromethane to dichloromethane/methanol 95:5) gave the title compound as a yellowish solid (123 mg, 47%). *Prepared according to Sandosham J.; Undheim, K. Tetrahedron 1994, 50 (1), 275-284.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[CH:6]2[C:5](=[O:8])[C:4]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[C:3]([O:2][CH3:1])[CH2:7]2)[CH2:28][CH2:27]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Reactant: O=CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152 %

Procedure:
To a stirred solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (0.69, 3.0 mmol) in anhydrous THF (10 ml) at −78 C under an N2 atmosphere was added dropwise a solution of lithium diisopropylamide (1.75 ml of a 1.8M solution in THF/heptanes/ethyl benzene, 3.15 mmol). The reaction was stirred at −78 C for 60 minutes and then cyclopropanecarbaldehyde (0.27 ml, 3.6 mmol) was added dropwise. The reaction was stirred at −78 C for a further 30 minutes and then allowed to warm to room temperature over 210 minutes. The reaction was quenched by addition of H2O (50 ml) and extracted with EtOAc (50 ml). The organic phase was washed with H2O (50 ml) and brine (50 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give a brown oil (1.37 g). The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product (mix of diastereomers) as a colourless oil (622 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[N:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:16]1([N:13]2[CH2:14][CH2:15][N:10]([C:4]3[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=4)[N:3]=3)[CH2:11][CH2:12]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1cc(Cl)nc(N2CCN(C3CCCCC3)CC2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCN(C3CCCCC3)CC2)c1
Temperature: 100 °C

Procedure:
The nitrile 25E (2.2 g, 7.2 mmol), 4-trifluoromethylphenylboronic acid (2.05 g, 1.1 mol eq), palladium acetate (45 mg), cesium carbonate (4.5 g, 2 mol eq), and XPhos (190 mg) were mixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added. The mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×20 mL) and concentrated under reduced pressure. The residue was a yellow oil. 1HNMR (DMSO, 200 MHz) δ 1.14 (bm, 4H), 1.59 (bm, 1H), 1.75 (bm, 4H), 2.26 (bm, 2H), 2.58 (m, 4H), 3.62 (m, 4H), 7.33 (s, 1H), 7.66 (s, 1H), 7.82 (d, 2H, J=8.2), 8.28 (d, 2H, J=8.2).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:29]([C:33]1[CH:34]=[C:35]([CH:45]=[CH:46][CH:47]=1)[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O)([CH3:32])([CH3:31])[CH3:30]>>[CH2:25]([N:24]1[C:19]2[CH:18]=[C:17]([O:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][C:20]=2[N:23]=[C:40]1[C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([O:36][C:35]2[CH:45]=[CH:46][CH:47]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:34]=2)[CH:38]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNc1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CC(C)(C)c1cccc(Oc2cccc(C=O)c2)c1
Product: CCCCn1c(-c2cccc(Oc3cccc(C(C)(C)C)c3)c2)nc2ccc(OCCN3CCNCC3)cc21

Procedure:
A mixture of 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (synthesized via General Procedures G1 and G2 and H) (0.130 g, 0.512 mmol) and 3-(3-tert-butylphenoxy)benzaldehyde was subjected to General Procedure K. Reaction was concentrated and purified on silica gel-chromatography using DCM-2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.10 g).
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>C1CCCCC1.O1CCCC1>[Li:5][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: [Li]CCCC
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Yield: 100 %

Procedure:
A solution of 0.17 mole of lithium 2,2,6,6-tetramethyl piperidide is prepared by the addition of 0.17 mole of n-butyllithium (2.3 moles) in 74 ml of cyclohexane to 0.17 mole (28.7 ml) of 2,2,6,6-tetramethylpiperidine in 120 ml of tetrahydrofuran at a temperature below -20° C.
Reaction SMILES: [NH2:1][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][C:4]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH2:33]([O:35]CC)C>CC#N>[C:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][N:6]3[C:4](=[O:5])[CH2:3][CH:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:1][C:33]3=[O:35])[CH2:9][CH2:10]2)=[O:15])[CH2:17][CH2:18]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CCOCC
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CNC(=O)CC(N)c3ccccc3)CC2)CC1
Solvent: CC#N
Product: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN3C(=O)CC(c4ccccc4)NC3=O)CC2)CC1

Procedure:
A solution of 3-amino-N-[trans-4-(4-isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-3-phenyl-propionamide (0.13 g, 0.29 mmol) and 1,1-carbonyldiimidazole (0.10 g, 0.58 mmol) in CH3CN was irradiated with microwave at 100° C. (250 watt) for 10 minutes. The solvent was removed under reduced pressure and the residue was washed with H2O and then with diethylether, affording 31 mg of the titled compound (22% yield).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19](=[O:35])[C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19](=[O:35])[C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
2-(2-Fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)acetic acid is prepared from tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: NCCCCCC(=O)O
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1

Procedure:
Stir 1.0 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 0.78 g (5.94 mmol) 6-aminohexanoic acid and 1.5 ml DIEA in 10 ml DMF overnight at 120° C. Add the reaction mixture to water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated sodium chloride solution, dry over magnesium sulphate and concentrate by vacuum evaporation. Chromatograph the residue on silica gel (solvent: cyclohexane/ethyl acetate 2:1→1:2). 560 mg (43.7% of theor.) of the target compound is obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].[CH2:16]([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>C(#N)C>[C:8]([C:10](=[C:19]([OH:20])[CH:18]([CH2:22][CH3:23])[CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: CCC(CC)C(=O)Cl
Reactant: CCOC(=O)CC#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=C(O)C(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With ice-cooling, 227 g (2.15 mol) of triethylamine were poured into a solution of 170 g (1.5 mol) of ethyl cyanoacetate in acetonitrile, and 101 g (0.75 mol) of 2-ethylbutyryl chloride were added dropwise at from 10 to 25° C. After 2 h of stirring at 25° C., the mixture was concentrated and the residue was dissolved in MTBE (methyl tert-butyl ether). By washing with 5% strength NaOH, the enolate was transferred into the aqueous phase, from which it was released by acidification to pH 3. The acidic aqueous solution was extracted and the extract was dried and concentrated. Customary purification gave 100 g (63% of theory) of the title compound as an oil (b.p. 78 to 80° C./1.5 mbar).
Reaction SMILES: CS(O[CH:6](C)[C:7](OC)(OC)[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)(=O)=O.[C:25](=[O:28])(O)[O-:26].[Na+].CO>O>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:7]([CH3:6])[C:25]([OH:26])=[O:28])[CH:17]=[CH:16]2
Reactant: O=C([O-])O
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 70 °C

Procedure:
A mixture is prepared from the oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate, from Example 16, 20 g of sodium bicarbonate, 200 ml of methanol and 150 ml of water, and the mixture is heated at 70° C. with reflux for 14 hours. The methanol is removed under reduced pressure on a rotary evaporator and the oil remaining is extracted with ethyl ether. The organic and aqueous phases are separated and the aqueous phase is acidified with hydrochloric acid to afford 12.5 g of 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(CC(=O)C)C(C)=O.C(OCC)(=O)C.CCCCCC>C(O)(=O)C.C(OCC)(=O)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:14]2[CH3:13])[N:3]=1
Reactant: Cc1ccccc1
Reactant: Nc1cccc(Br)n1
Agent: CC(=O)CCC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cccc(Br)n1
Yield: 47 %

Procedure:
To a 1 L round-bottomed flask equipped with Dean-Stark trap, condenser, and nitrogen inlet were added 21.3 g (123 mmol) 2-amino-6-bromopyridine, 400 mL toluene, 14.1 g (123 mmol) acetonylacetone, and 20 drops acetic acid. The reaction was refluxed 5 days (tlc in 1/1:ethyl acetate/hexane, Rf=0.8(product), 0.5 (starting material)), cooled, poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using 5% methanol in methylene chloride to afford 14.4 g(47%) of the product as a low-melting yellow solid.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:32]=[CH:31][C:10]([O:11][C@H:12]([CH:14]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:13])=[CH:9][CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C>O1CCCC1>[Si:24]([O:23][CH:14]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:12]([CH3:13])[O:11][C:10]1[CH:31]=[CH:32][C:7]([B:37]([OH:38])[OH:36])=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: C[C@H](Oc1ccc(Br)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(B(O)O)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyllithium (2.5 ml, 1.7M in hexanes) was added over a 1 hour period to a solution of (2S,3RS)-2-(4-bromophenoxy)-3-tert-butyldimethylsilyloxy-5-pyridin-3-ylpentane (1.60 g, Example 5b)) and triisopropylborate (1.07 ml) in tetrahydrofuran (25 ml) at −78° C. The resulting solution was stirred at −78° C. for 2 hours and was then quenched by the addition of a saturated solution of ammonium chloride in water (50 ml). The mixture was poured into water (50 ml) and extracted into ethyl acetate (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with ethyl acetate and then ethyl acetate:methanol (4:1) to afford the sub-title compound as a foam (1.2 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16]=[C:17]1O[C:19](=[O:20])[CH2:18]1.C(Cl)Cl>CCOCC>[CH3:1][N:2]1[C:17]([CH3:16])=[CH:18][C:19](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Reaction time: 117 h

Procedure:
10.25 g of ethyl beta-methylaminocinnamate, 9.4 g of technical grade diketene and 25 ml dry methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The reaction mixture is stored at room temperature for 117 hours. Approximately 75 ml of dry ether is added and the resulting crystalline solid is filtered to yield 8.5 g of ethyl 1,6-dimethyl-2-phenyl-4-oxonicotinate. mp (toluene)=244°-248° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=O.C(O[SiH](OCC)OCC)C>C1C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C(Cc1cccs1)N1CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Solvent: c1ccccc1
Product: C(=CN1CCOCC1)c1cccs1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
4-(2-[2-thienyl]acetyl) morpholine (0.42 g, 2.0 mmol) was dissolved in C6H6 (4 mL) and then triethoxysilane (0.92 mL, 5.0 mmol) and titanium (IV) isopropoxide (0.03 mL, 0.1 mmol) were added. The reaction mixture was heated to 60 ° C. for 15 hours. The C6H6 was removed in vacuo and the resulting yellow solid was dissolved in warm (60° C.) hexane (4 mL). The hexane solution was cooled to room temperature, and yellow crystals appeared in the flask. The recrystallization flask was put in an acetone-filled dewar, which was cooled to -78° C. overnight. The hexane solution was decanted from the yellow crystals. The crystals were washed with cold hexane (3 mL) and recrystallized from hot (60° C.) hexane. The flask containing the crystals was put in an acetone-filled dewar, which was cooled to -78° C. The hexane was decanted and the crystals were washed with 2 portions of cold hexane (1 mL). The crystals were dried in vacuo and 0.28 g (74% yield) of 4-(2-[2-thienyl]ethenyl) morpholine, as yellow crystals, was collected.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[I:19])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:14]=[C:13]4[I:19])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C1=COCCC1
Reactant: Ic1n[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Ic1nn(C2CCCCO2)c2ccc(-c3cncc(C4CC4)n3)cc12
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indazole (192 mg, 0.53 mmol), 3,4-dihydro-2 h-pyran (96 μL, 1.06 mmol) and p-toluenesulfonic acid monohydrate (20 mg, 0.106 mmol) in THF (3 mL) was heated at reflux overnight (9 h). After cooling to RT, the mixture was concentrated to about 1 mL. The mixture was diluted with EtOAc and saturated NaHCO3 (aq.) and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-30% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (140 mg, 0.31 mmol, 59% yield) as a pale yellow foam. MS (ESI, pos. ion) m/z: 447.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[O:15]1[C:14]2[CH:19]=[CH:20][C:11]([N:7]3[CH2:6][CH:5]([CH2:4][CH2:3][CH:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=5)[N:26]=[CH:25][CH:24]=4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2nccc(CCC(N)CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Solvent: ClCCl
Product: COc1ccc2nccc(CCC(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)NS(C)(=O)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of the compound of Example 116 (0.05 g, 0.1 mmol) in DCM (2 mL) at rt was treated sequentially with TEA (0.03 mL, 2 eq.) and MsCl (0.013 mL, 1.5 eq.). The mixture was stirred at rt for 2 h, washed with water and purified by FC (EA, EA/MeOH 9:1) to give the title compound as a colourless foam (0.052 g, 89% yield).