Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:37]([NH2:45])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24]([NH:45][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)OCC
Yield: 49.4 %

Procedure:
A solution of 1.75 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate, 0.46 mL (3.7 mmol) of phenethylamine, in 20 mL of dimethylformamide is heated at 80° C. for 2 hours. After addition of water, the reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.7 g (50%) of ethyl (Z)-2-ethoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylate is obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.Cl.[O:32]([NH2:34])[CH3:33].C(=O)(O)[O-].[K+]>O>[CH3:33][O:32][N:34]=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(CC=NOC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2 h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, was filtered and was concentrated to give 3-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal O-methyloxime as a mixture of isomers (70 mg, 90%) crude product. LC/MS (M+H)+: m/z=429.
Reaction SMILES: C(C(C=O)=[O:10])=CC1C=CC=CC=1.[Se](=O)(O)O.C1(C=CC(=O)C)C=CC=CC=1.O=C(CCCCCCCC(O)=O)CC(O)=O.O=C(CCCCCCCC(OC)=O)CC(OC)=O.[OH-].[K+:63].[C:64]1([CH:70]=[CH:71][C:72](=O)[CH:73]([OH:87])[CH2:74][C:75](=[O:86])[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][C:83]([OH:85])=[O:84])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[OH-:10].[K+:63].[OH:87][CH:73]1[CH2:74][C:75](=[O:86])[C:76]([CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][C:83]([OH:85])=[O:84])=[C:72]1[CH:71]=[CH:70][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: O=C(O)CCCCCCCC(=O)CC(O)C(=O)C=Cc1ccccc1
Reactant: O=CC(=O)C=Cc1ccccc1
Agent: CC(=O)C=Cc1ccccc1
Agent: COC(=O)CCCCCCCC(=O)CC(=O)OC
Agent: O=C(O)CCCCCCCC(=O)CC(=O)O
Product: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O

Procedure:
Starting materials suitable for the manufacture of the compounds of this invention are styrylglyoxal, conveniently prepared by the selenous acid oxidation of 4-phenyl-3-buten-2-one, and the dialkyl esters of 3-oxoundecane-1,11 -dioic acid. Dimethyl 3-oxoundecane-1,11-dioate is thus saponified with potassium hydroxide and the resulting dicarboxylic acid is allowed to react with styrylglyoxal, thus affording 14-phenyl-9,12-dioxo-11-hydroxytetradec-13-enoic acid. Cyclization of the latter intermediate in the presence of potassium hydroxide results in the instant 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][NH:4][C:3]=1[C:11]([O:13]C)=O.[OH-].[Li+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][CH2:51][C:52]1[C:53]([F:69])=[C:54]([O:59][C:60]2[CH:61]=[C:62]([CH:65]=[C:66]([Cl:68])[CH:67]=2)[C:63]#[N:64])[C:55]([Cl:58])=[CH:56][CH:57]=1>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][NH:4][C:3]=1[C:11]([NH:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([O:59][C:60]2[CH:61]=[C:62]([C:63]#[N:64])[CH:65]=[C:66]([Cl:68])[CH:67]=2)[C:53]=1[F:69])=[O:13]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CNC(=O)c1c[nH]c(C(=O)OC)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c[nH]c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c1Cl
Temperature: 35 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of methyl 3-chloro-4-[(methylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.04 g, 0.185 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.044 g, 1.847 mmol). The reaction mixture was stirred overnight at 35° C. The solvent was evaporated and the resulting solid placed under high vacuum. To the intermediate mixture was added DMF (1 mL), HATU (0.084 g, 0.222 mmol), DIPEA (0.048 ml, 0.277 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.057 g, 0.185 mmol). The solution was stirred for 1.5 h at RT. Purification was accomplished by HPLC. The desired fractions were neutralized with saturated sodium bicarbonate, extracted with EtOAc (3×5 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to afford 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N4-methyl-1H-pyrrole-2,4-dicarboxamide (0.028 g, 31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.14 (br. s., 1H) 8.13 (t, 1H) 7.81 (d, 1H) 7.74-7.79 (m, 1H) 7.44-7.53 (m, 3H) 7.35 (t, 1H) 7.40 (d, 1H) 4.54 (d, 2H) 2.68 (d, 3H). MS: m/z 495.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(Br)ccc2n1

Procedure:
A solution of 2-chloro-6-bromoquinoline (4.0 g) in methanol (20 cm3) was heated under reflux with sodium methoxide [made from sodium (0.5 g) and methanol (20 cm3)] for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water (20 cm3) and chloroform (100 cm3). The aqueous phase was extracted with chloroform (2×30 cm3) and the dried (MgSO4) extracts were evaporated to give a solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield 2-methoxy-6-bromoquinoline, m.p. 93°-96°, (3.0 g).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:22][C:23]1[C:28]2[S:29][C:30]([C:32]3[C:37]([Cl:38])=[CH:36][C:35](I)=[CH:34][C:33]=3[Cl:40])=[N:31][C:27]=2[CH:26]=[CH:25][N:24]=1>CN(C)C(=O)C.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:35]2[CH:36]=[C:37]([Cl:38])[C:32]([C:30]3[S:29][C:28]4[C:23]([Cl:22])=[N:24][CH:25]=[CH:26][C:27]=4[N:31]=3)=[C:33]([Cl:40])[CH:34]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)c(-c3nc4ccnc(Cl)c4s3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
Zinc dust (0.116 g, 1.77 mmol) and celpure P65 (0.025 g) were stirred under an argon atmosphere for 30 minutes. N,N-dimethylacetamide (0.5 mL) was added followed by 1,2-dibromoethane (0.014 mL, 0.163 mmol) and trimethylsilyl chloride (0.021 mL, 0.163 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then a solution of 3-iodoazetidine-1-carboxylic acid tert-butyl ester (0.385 g, 1.36 mmol) in N,N-dimethylacetamide (1 mL) was added and stirring at room temperature was continued for 1.5 hours. The resultant mixture was filtered and the filtrate was added to a suspension of 4-chloro-2-(2,6-dichloro-4-iodophenyl)-thiazolo[5,4-c]pyridine (0.30 g, 0.68 mmol), PdCl2(dppf)•DCM (0.052 g, 0.068 mmol) and CuI (0.016 g, 0.088 mmol) in N,N-dimethylacetamide (4 mL) previously degassed with a stream of argon. The reaction mixture was heated at 80° C. for 2 hours and then allowed to cool to room temperature. The crude mixture was partitioned between diethyl ether and water and the aqueous phase was extracted with diethyl ether (×2). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-70% Et2O in petroleum ether to afford the title compound as an off-white solid (108 mg, 34%). LCMS (Method D): RT=4.66 min, m/z: 470 [M+H+].
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]1[N:8]2[C@H:9]([CH3:25])[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]1)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:21]([O:20][C:18]([N:11]1[CH2:10][C@@H:9]([CH3:25])[N:8]2[C@H:13]([CH2:14][C:15]3[C:7]2=[N:6][C:5]([CH2:3][OH:2])=[CH:17][CH:16]=3)[CH2:12]1)=[O:19])([CH3:23])([CH3:22])[CH3:24]
Reactant: COC(=O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Yield: 67.3 %

Procedure:
A solution of 4.2 g (12.1 mmol) (4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2,6-dicarboxylic acid 2-tert-butyl ester 6-methyl ester in 100 ml tetrahydrofuran was cooled to 0 deg C. and treated dropwise with 48.4 ml diisobutylaluminium hydride (48.4 mmol; 1M solution in THF). The cooling bath was removed and after 1 h at room temperature the reaction was quenched with a 10% aqueous potassium sodium tartrate solution and ethyl acetate was added. The two-phase system was filtered through a bed of dicalite speed plus; the filtrate was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After filtration and evaporation the residue was purified by chromatography on silica gel (0.032–0.062 mm) with ethyl acetate as eluant to afford the desired product as a light yellow foam (67.3%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C.[CH3:30][NH:31][CH3:32]>CO>[CH3:30][N:31]([CH3:32])[C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:3]
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reactant: CNC
Solvent: CO
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)N(C)C)s3)c2cc1OC

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid dimethylamide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (48.8 mg, 0.12 mmol) and dimethyl amine in methanol (2 molar) as described above in the general amide formation procedure. Product was isolated by preparative HPLC:15 mg, 30%. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H); 7.84 (s, 1 H); 7.73-7.79 (m, 2H); 7.44-7.59 (m, 3 H); 7.40 (s, 1 H); 3.91 (s, 3 H, NCH3), 3.86 (s, 3 H); 3.01 (s, 3 H); 2.74 (s, 3 H). MS M/z 409 (M+1).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[O:38][CH:37]=[N:36][CH:35]=5)[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:7]=1)=O.[Li+].[OH-].C1COCC1>O>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[O:38][CH:37]=[N:36][CH:35]=5)[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Yield: 78.6 %

Procedure:
A solution of 2,2,2-trifluoro-N-{3-[3-(2-{[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}acetamide (0.89 g, 0.002 mols) and 1M LiOH (8.22 mL, 0.008 mols) in 10:1 THF:water (20 mL) was heated at 60° C. for 5 h. The reaction was washed with brine (25 mL), organic layer separated, aqueous layer extracted with EtOAc (25 mL), organic layers combined, filtered through a cotton plug, and solvent removed by rotary evaporation. The crude product was purified by column chromatography (5%-75% EtOAc in hexanes then 100% EtOAc) to provide the aniline (0.70 g, 96%) as a pale yellow foam. ES-LC/MS m/z=446 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[OH-].[K+].BrCCC>CS(C)=O>[C:3]([OH:27])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCBr
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 233.9 %

Procedure:
A solution of the 4-[(3-hydroxy,5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7, 433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C., and treated with a solution of bromopropane (118 mL, 1.30 mmol) in DMSO (1mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was adjusted to pH=3 with 1M HCl and extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated. Purification by silica gel radial chromatography (20:1=hexanes:Et2O) gave 4-[2-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid 337 mg (75%) as a coloreless oil: 1H NMR (400 MHz, CDCl3) δ8.15 (½ABq, J=8.2 Hz, 2H, ArH), 7.85 (½ABq, J=8.2 Hz, 2H, ArH), 7.46 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.78 (t, J=6.3 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.36 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3), 0.62 (t, J=7.4 Hz, 3H, CH3). The propoxyketo acid (1.34 mg, 0.33 mmol) in EtOH (2mL) was converted to the oxime derivative as described in Example 4 to provide, after recrystallization (CH2Cl2/hexanes (4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (109) (97%) as a white solid: mp 251-255° C. (d); 1H NMR (400 MHz, CDCl3) δ7.98 (½ABq, J=8.4 Hz, 2H, ArH), 7.54 (½ABq, J=8.4 Hz, 2H, ArH), 7.13 (s, 1H, ArH), 6.86 (s, 1H, ArH), 3.81 (t, J=6.2 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.51 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3), 0.72 (t, J=7.4 Hz, 3H, CH3).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:19]([CH3:25])[C:20](OCC)=[O:21])=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:19]([CH3:25])=[CH:20][OH:21])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(=CO)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 79.7 %

Procedure:
Diisobutylaluminum hydride (80 mL of 1M solution, 80 mmol) was added to a solution of ethyl 3,3-bis(4-fluorophenyl)-2-methylpropenoate (8.0 g, 26.5 mmol).in 75 mL dichloromethane at -70° C. After stirring for 4 hours the solution was quenched with 1N hydrochloride acid. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 5.5 g of the title compound as a clear oil. MS(EI): m/e =260 for M+ of C16H14F2O.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:23])[CH:21]=[CH2:22].O[C:25]1[NH:29][N:28]=[C:27]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[CH:26]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[CH2:20]([O:23][C:25]1[NH:29][N:28]=[C:27]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[CH:26]=1)[CH:21]=[CH2:22]
Reactant: C=CCO
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)[nH]n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCOc1cc(N2C(=O)c3ccccc3C2=O)n[nH]1

Procedure:
To a mixture of triphenylphosphine (2.75 g, 10.5 mmol), allyl alcohol (0.714 ml, 10.5 mmol), and 2-(5-hydroxy-1H-pyrazol-3-yl)isoindoline-1,3-dione (2.000 g, 8.73 mmol) in DMF (25 mL) at RT was slowly added DIAD (2.04 ml, 10.5 mmol). After 18 hrs the solution was concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic fraction was dried with sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography using 40-70% Hexanes:EtOAc to afford 2-(5-(allyloxy)-1H-pyrazol-3-yl)isoindoline-1,3-dione as a light yellow solid. MH+=270.1. Step 2B: To a mixture of 2-(5-(allyloxy)-1H-pyrazol-3-yl)isoindoline-1,3-dione (0.684 g, 2.54 mmol) in EtOH (10 mL) at RT was added anhydrous hydrazine (0.319 ml, 10.2 mmol). The solution was heated at 50° C. for 18 hrs before cooling to 0° C. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo to afford crude 5-(allyloxy)-1H-pyrazol-3-amine that was advanced without further purification. MS: Found M+H+=147.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:36][C:37]1[C:42](B(O)O)=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:28]1([CH3:33])[CH2:27][N:26]([C:15]2[CH:14]=[CH:13][C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:42]5[C:37]([F:36])=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:8][CH:9]=4)[C@@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:31][CH2:30][O:29]1
Reactant: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)CCO1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)CCO1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A 25 mL RB flask was charged with (R)-2-amino-2′-(2,2-dimethylmorpholino)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (270 mg, 0.526 mmol), tetrakis(triphenylphosphine)palladium(0) (60.8 mg, 0.053 mmol), 2-fluoropyridin-3-ylboronic acid (119 mg, 0.841 mmol), DMF (2629 μL) and sodium carbonate (2M solution) (789 μL, 1.577 mmol). The mixture was stirred under argon for 2 hrs at 85° C. The mixture was diluted with water (2 ml) and extracted with 10 ml of EtOAc. The organic layer was washed with water, brine, passed through plug of Celite and concentrated. Dark residue was purified by silica gel chromatography on a 12 g RediSep column using 5-70% DCM/MeOH/NH4OH in DCM to afford (S)-2′-(2,2-dimethylmorpholino)-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine. Found MS: MH+=461.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21](OCC)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnn2c(C)cccc12
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cccc2c(C(=O)OC3CN4CCC3CC4)cnn12
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
After a suspension of 370 mg (2.9 mmol) of 3-quinuclidinol (product of Aldrich Chemical Co., Inc.) in 30 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.1 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours. Unreacted sodium was removed and 200 mg (0.98 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 240 mg (0.84 mmol) of the title compound were obtained as white crystals (yield: 86%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[I-:6].[Na+].Br[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CC(C)=O>[I:6][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: [I-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(CI)OCC

Procedure:
To a solution of sodium bicarbonate (426.2 g, 5074 mmol) in acetone was added sodium iodide (760.3 g, 5074 mmol) and 2-bromo-1,1-diethoxyethane (500 g, 2537 mmol). The reaction mixture was allowed to reflux for 8 hours. The reaction mixture was then filtered and the solvent evaporated. Ether was added and the reaction mixture filtered again. The ether was evaporated, leaving the title compound, 2-iodo-1,1-diethoxyethane, as an oil, which was further purified by column chromatography.