Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].O.CO[CH2:46][CH2:47]OC>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>[CH3:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=3)[N:9]=2)[N:12]=[C:13]([CH:46]=[CH2:47])[CH:14]=1
Reactant: COc1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Reactant: COCCOC
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: [K+]
Solvent: O
Product: C=Cc1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.30 g, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol, 10 mol %) in 1,2-dimethoxyethane (4 mL) was stirred under an argon atmosphere for 10 min, then was sequentially treated with K2CO3 (0.075 g, 0.54 mmol, 1.0 eq), water (1.5 mL) and vinylboronic acid anhydride pyridine complex (prepared as described in J. Org. Chem. 2002, 67, 4968; 0.13 g, 0.54 mmol, 1.0 eq). The resulting mixture was heated at the reflux temperature for 16 h, then was added to water (15 mL). The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 1.5 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 2.0 min, gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give tert-butyl {1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.25 g, 92%):
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3CO)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3[O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])=[N:27][N:28]=2)[CH:25]=1
Reactant: OC[C@H]1CCCN1c1nnc2ccc(F)cn12
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CCCN1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (430 mg, 1.40 mmol) was added to a solution of Intermediate 27a (220 mg, 0.93 mmol) and Et3N (190 mg, 1.86 mmol) in a DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (170 mg, 47%). LCMS (Method 1): Rt 4.45, m/z 393 [MH+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][OH:34])[CH:30]=2)[NH:25][C:24]=1[C:35]([F:38])([F:37])[F:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])[CH:30]=2)[NH:25][C:24]=1[C:35]([F:37])([F:36])[F:38])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)c1c(C(F)(F)F)[nH]c2ccc(CCO)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2[nH]c(C(F)(F)F)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.1 mL, 1.15 mmol, 1 eq) and triethylamine (0.32 mL, 2.30 mmol, 2 eq) were added to 5-(2-hydroxy-ethyl)-2-trifluoromethyl-1H-indole-3-carboxylic acid benzyl ester (420 mg, 1.15 mmol, 1 eq) obtained from previous step in THF (50 mL) solution in 100-mL round bottom flask at room temperature. The reaction mixture was stirred at room temperature for 3 hours (followed by TLC). After the solvent was removed, the residue was dissolved in ethyl acetate (100 mL), and then washed with sat NaHCO4 and brine respectively. The organic layer was dried over MgSO4, and concentrated to give a pale brown solid. The crude was carried over to the next step.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[F:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[F:48])[C:41](=O)[CH2:42]Br>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:42]=[C:41]([C:40]2[CH:45]=[CH:46][C:47]([F:48])=[C:38]([F:37])[CH:39]=2)[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(-c3ccc(F)c(F)c3)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3,4-difluorophenacyl bromide.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1.CN(C=O)C>O>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:31]4[CH2:32][CH2:33][O:28][CH2:29][CH:30]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(C3=CCOCC3)cc12

Procedure:
A vial was charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (380 mg, 1.091 mmol), potassium carbonate (754 mg, 5.46 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (688 mg, 3.27 mmol), pd(ph3p)4 (126 mg, 0.109 mmol), DMF (5457 μL), and water (2.5 mL). The vial was sealed, placed in 80° C. and heated overnight. The mixture was diluted with water (35 mL) and extracted with EtOAc (3×15 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 80-g Redi-Sep column, eluting with 0-100% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an orange solid.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:33])([F:32])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][C:5]1[CH:13]=[CH:14][C:2]([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:32])[F:33])=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(CCCC2CCNCC2)cc1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(CCCC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
2-(4-Iodophenoxy)tetrahydropyran (1.12 g, 3.7 mmol) and 4-[3-(4-trifluoromethylphenyl)propyl]piperidine (1 g, 3.7 mmol) were dissolved in degassed anhydrous toluene (10 ml). Sodium tert-butoxide (0.50 g, 5.2 mmol), tri-tert-butylphosphine tetrafluoroborate (tBu3P.HBF4) (0.09 g, 0.3 mmol) and palladium acetate (0.03 g, 0.15 mmol) were added thereto, and the mixture was heated at reflux under a nitrogen atmosphere for 5 hours. After being allowed to cool to room temperature, water (10 ml) was added to the mixture, followed by extraction with ethyl acetate. The organic layers were combined and washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After removing insoluble matter by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to afford the title compound as a pale yellow solid (1.42 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[N-:19][Si](C)(C)C.[Li+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]([NH2:19])=[NH:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N=C(N)c1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Referring to Reaction Scheme 4, Stage 1, to a stirred solution of 6-(3,4-dichloro-phenyl)-pyrimidine-4-carbonitrile (1 eq) in anhydrous toluene (20 vol) at 0° C. was added lithium hexamethyldisilazide (2 eq) and the reaction mixture was stirred at ambient temperature for 2 hours under an atmosphere of nitrogen. The reaction mixture was cooled to 0° C. and quenched with HCl (3M). After 30 minutes stirring, water (40 vol) was added, followed by toluene (20 vol). The mixture was partitioned and the precipitate present in the aqueous phase was filtered off. The solid was suspended in a 3M solution of sodium hydroxide, stirred at room temperature for 30 minutes to give 6-(3,4-dichloro-phenyl)-pyrimidine-4-carboxamidine, which was used in the next stage without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].[CH:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[O:12][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=1)[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)cc(OC)c1O
Reactant: CC(C)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C=O)cc(OC)c1OCc1ccc(C(C)C)cc1

Procedure:
The crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=1)C(OCC)=O)[CH3:2].[Li+].[Cl-].CS(C)=O.Cl>O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(6-Chloro-3-nitro-pyridin-2-yl)-malonic acid diethyl ester (32.45 g, 103 mmol), LiCl (16.18 g, 268 mmol), H2O (10 mL), and dimethyl sulfoxide (50 mL) is stirred at 120° C. for a period of 24 h. The mixture is cooled to room temperature and diluted with H2O (400 mL). 1 N HCl (aq.) is added until all of the solids are dissolved. The mixture is extracted with EtOAc (5×150 mL), and the combined organic extracts washed with H2O (2×100 mL), then brine (100 mL), and dried over Na2SO4. The mixture is filter to remove the solids, concentrated, and purified by flash chromatography on silica (elute with 5% EtOAc in hexanes) to give the title compound as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.39 (d, 1H, J=8.7 Hz), 7.47 (d, 1H, J=8.7 Hz), 4.28 (s, 2H), 4.19 (q, 2H, J=7.1 Hz), 1.27 (t, 3H, J=7.1 Hz); 13C (100 MHz, CDCl3) δ 168.7, 166.8, 154.8, 151.4, 135.9, 124.4, 61.7, 41.9, 14.3; MS (CI) m/z 255.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([NH2:13])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH:2]([NH:13][CH:19]2[CH2:18][CH2:17][C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([N:15]([CH3:29])[CH3:14])[CH2:21][CH2:20]2)[CH3:1])=[CH:5]1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
DL-α-Methyltryptamine (348 mg, 2 mmol) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (229 μl), the mixture was stirred for one hour at RT. Sodium triacetoxyborohydride (550 mg) was then added and the suspension was stirred for four days at RT. For working up, water (15 ml) was added to the reaction mixture. The clear phases were separated and the aqueous phase was washed with ether (10 ml) and then rendered strongly alkaline with sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (4×10 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (723 mg) was recrystallized twice from a mixture of ethyl acetate/cyclohexane (2 ml/6 ml). A fraction of the nonpolar diastereoisomer of N′-[2-(1H-indol-3-yl)-1-methyl-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (128 mg, m.p. 155-162° C.) was obtained.
Reaction SMILES: Cl.Cl.[C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.[NH3:25]>CO.C1(C)C=CC=CC=1>[NH2:25][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[CH:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: N
Reactant: COC(=O)CC(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C=C(N)c1cccnc1
Temperature: 62.5 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A suspension of methyl nicotinoylacetate dihydrochloride (50.0 g, 0.23 mol, dried) and sodium acetate (19.0 g, 0.23 mol) in glacial acetic acid (1.4 g, 0.02 mol), toluene (50 g), and methanol (50 g) was heated to 60-65° C. Ammonia (14.0 g, 0.82 mol) was bubbled through the suspension. After four hours, no starting material was present by HPLC. Two-thirds of the solvents were removed by distillation. The solution was stirred at 0° C. for one hour, and the precipitate was collected by filtration and dried to yield 83% of methyl 3-amino-3-(3-pyridyl)-2-propenoate. The crude product was used as is without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:43][O:44]C(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:49]([OH:51])=[O:50])[CH2:43][OH:44])=[O:38])=[CH:29][CH:28]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CO)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Ser(tBu)-OtBu (51 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.72-13.24 (br.s, 1 H), 8.95 (s, 1 H), 8.28-8.51 (br.s, 1 H), 7.91 (d, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.27 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.64 (m, 2 H), 2.91 (s, 3 H), 2.56 (m, 2 H), 2.39 (s, 3 H), 2.17 (m, 2 H), 1.78 (m, 2 H); MS (APCI+) m/z 646 (M+H)+.
Reaction SMILES: FC1C=CC(F)=C2C=1C=CCO2.[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[C:16]([F:24])[CH:15]=1>>[F:13][C:14]1[CH:15]=[C:16]([F:24])[CH:17]=[C:18]2[C:19]=1[CH:23]=[CH:22][CH2:21][O:20]2
Reactant: C#CCOc1cc(F)cc(F)c1
Agent: Fc1ccc(F)c2c1C=CCO2
Product: Fc1cc(F)c2c(c1)OCC=C2
Yield: 22.2 %

Procedure:
This compound was prepared analogously to 5,8-difluoro-2H-chromene but using (18 g, 107 mmol) of 1,3-difluoro-5-prop-2-ynyloxybenzene and PEG-200 as solvent to give the title compound (4 g, 23%).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:20][CH2:21][CH3:22])([C:6]1[N:11]2[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].C.P(CC1C2N(C=C(C(O)=O)N=2)C=CC=1)(O)(O)=O.O1CCOCC1.[Cl:47]Cl>CCOCC>[ClH:47].[CH2:1]([O:3][P:4]([O:20][CH2:21][CH3:22])([C:6]1[N:11]2[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: ClCl
Agent: CCOC(=O)c1cn2c(P(=O)(OCC)OCC)cccc2n1
Agent: O=C(O)c1cn2cccc(CP(=O)(O)O)c2n1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cl

Procedure:
The product from Example 51 (1.6 g, 4.4 mmol) was dissolved in CH2 Cl2 (30 mL), treated with activated charcoal and filtered. To this filtrate was then added 6N HCl in dioxane (0.9 mL, 4.4 mmol) followed by Et2O (100 mL). The precipitated product was filtered, washed with Et2O, and dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:31])([CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C@@H:20]([OH:30])[CH2:21][CH2:22]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5].[CH2:32]([O:34]C(=O)C(CC(F)(F)C[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(C[C@@H](OC4CCCCO4)CC2)=CC3)CC1)C)C(OCC)=O)[CH3:33].CC1C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>CO.C(OCC)(=O)C.N1C=CC=CC=1>[C:32]([O:30][C@H:20]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18](=[CH:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][C:2]([F:31])([F:1])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5])[CH2:19]1)(=[O:34])[CH3:33]
Reactant: C[C@H](CC(F)(F)CC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(=O)C(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC(F)(F)CC(C)(C)O)[C@@]4(C)CC[C@@H]32)C1
Yield: 96 %

Procedure:
The THP-ether (13) (26 mg, 0.0498 mmol) in methanol (4 ml) and THP (9) (4 ml) was treated with a catalytic amount of TsOH at room temperature for 1 hr. The usual work-up (ethyl acetate for extraction) gave the crude diol (21.4 mg). This diol was treated with acetic anhydride (1 ml) and pyridine (1 ml) at room temperature for 14 hr. The usual work-up (ethyl acetate for ertraction) gave a crude product, which was applied to a column of silica gel (5 g). Elution with benzene-ethyl acetate (10:1) provided the acetate (14) (23.0 mg, 96%); mp 168°-170° C. (methanol). 1H-NMR δ: 0.82 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.07 (3H, d, J=6 Hz, 21-H3), 1.35 (6H, s, 26-H3 and 27-H 3), 2.03 (3H, s, acetyl), 4.55 (1H, m, 3-H), 5.36 (1H, m, 6-H). High resolution MS Calcd for C27H42F2O (M+ --CH3COOH): 420, 3202. Found: 420, 3206.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:23]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[CH:23]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1cc(-c2cn3ccccc3n2)ccc1-c1ccccn1
Agent: [Pd]
Solvent: CO
Product: COc1cc(-c2cn3c(n2)CCCC3)ccc1-c1ccccn1
Reaction time: 72 h

Procedure:
A solution of 2-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[1,2-a]pyridine (40 mg, 0.13 mmol) in methanol (2 mL) was treated with Pd/C (8 mg of 10%) and stirred vigorously under an atmosphere of hydrogen gas for 3 days. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to afford the desired 2-(3-methoxy-4-pyridin-2-ylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 8.88 (d, 1H), 8.69 (m, 1H), 8.35 (d, 1H), 8.09 (m, 2H), 7.86 (m, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 4.28 (br s, 2H), 4.09 (s, 3H), 3.17 (br s, 2H), 2.15 (br s, 4H) ppm. MS (ESI) 306 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:19])[CH2:17][OH:18])[CH:13]=[C:12]([C:20]([O:22]C)=[O:21])[CH:11]=1)#[N:2].[OH-].[Li+].[NH4+].[Cl-]>O1CCOCC1.O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:19])[CH2:17][OH:18])[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2C#N)cc(C(O)CO)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)CO)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of methyl 2′-cyano-5-(1,2-dihydroxyethyl)-4′-methylbiphenyl-3-carboxylate (140 mg, 0.45 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was added lithium hydroxide (40 mg, 1.67 mmol). The reaction mixture was stirred at rt for 6 h, and then treated with aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, and concentrated to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.21 (m, 1H), 8.13 (m, 1H), 7.87 (m, 1H), 7.73 (s, 1H), 7.66-7.61 (m, 1H), 7.58 (d, 1H, J=7.6 Hz), 4.91 (dd, 1H, J=7.2, 4.4 Hz), 3.75 (dd, 1H, J=11.2, 4.4 Hz), 3.65 (dd, 1H, J=11.2, 7.2 Hz), 2.47 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17]Br)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.0 g) in N,N-dimethylformamide (100 mL) were added tert-butyl(2-bromoethyl)carbamate (12 g) and cesium carbonate (19 g), and the mixture was stirred overnight at 40° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13 g).