Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[S:26])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[N:9]=[CH:8][C:7]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:15])=[C:6]2[OH:25].[C:27]1(C)C=CC(S(O)(=O)=O)=C[CH:28]=1.C(OC(OCC)CBr)C>C(O)(=O)C.C(OCC)(=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:25])=[CH:4][C:3]([C:2]2[S:26][CH:27]=[CH:28][N:1]=2)=[CH:12][C:11]=3[F:13])=[O:15])=[CH:19][CH:20]=1
Reactant: NC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(CBr)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(-c3nccs3)cc2c1O
Temperature: 100 °C
Yield: 544.9 %

Procedure:
To a suspension of the title compound of Example 52 (0.14 g) and p-toluenesulfonic acid (0.0084 g) in 2 mL acetic acid is added bromoacetaldehyde diethyl acetal (0.08 mL). The reaction is heated at 100° C. for approximately 45 minutes. The reaction is cooled to room temperature and diluted with 30 mL ethyl acetate. The solid is filtered and dried to give the desired product (0.11 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[N:22]=[C:23]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[NH:24][CH:25]=1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH2:16][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[C:23]5[NH:24][CH:25]=[N:21][N:22]=5)=[O:29])[CH2:18][CH:19]4[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI): mass calculated for C25H23N7O, 437.50; m/z found 438.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 12.43 (br s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.08-7.91 (m, 3H), 7.60-7.42 (m, 5H), 7.39-7.31 (m, 1H), 6.98 (t, J=6.1 Hz, 1H), 4.01-3.87 (m, 2H), 3.85-3.65 (m, 3H), 3.61-3.40 (m, 2H), 3.28-2.89 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[N:3]1.[Cl:19]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (356 mg, 1.35 mmol) and N-chlorosuccinimide (180 mg, 1.35 mmol) in tetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (2.2 ml, 13.47 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (357 mg, 1.25 mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 271, 273 (M, M+2)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH:18]([CH3:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([CH3:28])[CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCC(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCC(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 38.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.0 g of 4-(2-ethoxy-1-methylethoxy)-benzyl bromide, and then 1.9 g of anhydrous potassium carbonate was added thereto. The mixture was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, procedures similar to those in Preparation Example 2 were carried out to obtain 1.5 g of the aimed product, m.p. 72.3°~73.1° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[CH2:31][NH2:32])[CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH:32][CH2:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:35][CH:34]=2)[CH2:25]1)=[O:33])=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCC(=O)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of (S)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give (S)-3-[N-{3,5-bis(trifluoromethyl)benzoyl}glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 5) (14.4 mg, 57%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 508.0 (M++H, C22H20ClF6N3O2).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([CH2:38]Cl)=[C:33]([O:40][CH3:41])[CH:32]=[CH:31]2.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([CH2:38][N:15]1[C:14](=[O:24])[C@@H:13]([NH:12][C:11](=[O:25])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH3:26])[CH2:19][O:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=3)=[C:33]([O:40][CH3:41])[CH:32]=[CH:31]2
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A mixture of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (1.1 g, 3.03 mmol, Eq: 1.00) (Example 1), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (951 mg, 3.33 mmol, Eq: 1.10), Cs2CO3 (1.08 g, 3.33 mmol, Eq: 1.10), and NaI (499 mg, 3.33 mmol, Eq: 1.1) in DMF (20 mL) was stirred for 3.5 at RT then heated at 50° C. for 1 h then at 60° C. for 30 min. The mixture was cooled, diluted with EtOAc, washed with water and brine. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (1.00 g, 1.63 mmol, 53.9%) as a light yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C@@H:10]([CH3:16])[C:9]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:18].[OH-].[Li+].O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C@@H:10]([CH3:16])[C:9]([OH:17])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1=O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Yield: 98.8 %

Procedure:
A solution of (3R,5S)-1-t-Butoxycarbonyl-5-carboxy-3-methylpyrrolidine-2-one (6.2 g, 25.5 mmol) in THF (50 mL) was treated with lithium hydroxide monohydrate (3 eq, 3.20 g) and water (5 mL). After stirring for 16 hr at room temperature the THF was removed in vacuo and water (20 mL) was added. The pH was adjusted to 3 by the addition of glacial acetic acid, ether (100 mL) was added and the layers separated. The aqueous phase was extracted with ether (3 x 100 mL) and the combined organic phases were washed with brine (400 mL), dried over Na2SO4, filtered and evaporated to dryness, azeotroping with toluene (3 x 15 mL). The residue was dried under high vacuum to give 6.58 g of the product (99%) as a white foam which was used without further purification: Rf 0.8 (1% formic acid in ethyl acetate, developed with ninhydrin). 1H NMR (200 MHz, D2O): δ 3.80 (dd, J=10.4, 4.7 Hz, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.60 (ddd, J=12.8, 4.2, 10.3 Hz, 1H), 1.25 (s, 9H), 1.0 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[C:9](OC2C=CC(F)=CC=2F)[C:8]([C:20](=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:7][N:6]=1.CCO.[NH2:34][NH2:35]>O1CCOCC1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:34][N:35]=[C:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:8]2=[CH:7][N:6]=1
Reactant: NN
Reactant: CC(C)CC(=O)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)Cc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 90 °C

Procedure:
1-[2,4-Bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-3-methyl-butan-1-one (0.427 g, 1.0 mmol) was dilloved in 10 mL of 10:1 dioxane:EtOH, and hydrazine (0.032 mL) was added. The reaction mixture was heated to 90° C. for four hours, then cooled and quenched by addition of 25 mL saturated aqueous ammonium chloride and 25 mL water. The aqueous mixture was extracted three times with 25 mL EtOAc, and the combined organic layers were washed with saturated aqueous brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was eluted through silica gel using 20% EtOAc in hexanes to yield 65 mg of 6-(2,4-difluoro-phenoxy)-3-isobutyl-1H-pyrazolo[3,4-d]pyrimidine as an oil. Mass Spec. M+H=305.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.ClCCl.C([O-])(=O)C.[K+].Br[C:40]1[S:41][C:42]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)=[C:47]([C@H:56]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:46]([CH3:67])=[CH:45][C:43]=2[N:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:63]([O:62][C@@H:56]([C:47]1[C:46]([CH3:67])=[CH:45][C:43]2[N:44]=[C:40]([C:2]3[N:7]=[C:6]4[N:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]4=[CH:4][CH:3]=3)[S:41][C:42]=2[C:48]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:57]([O:59][CH2:60][CH3:61])=[O:58])([CH3:64])([CH3:65])[CH3:66]
Reactant: Cc1cn(C)c2nc(Br)ccc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)cn(C)c4n3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-1,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.133 mmol) in dioxane (1.4 mL) was added bis(pinacolato)diboron (41 mg, 0.16 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (11 mg, 0.013 mmol), potassium acetate (39 mg, 0.4 mmol). The mixture was degassed and heated at 100° C. for 2 h. The mixture was cooled, and then added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (33 mg, 0.07 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol), K2CO3 (48 mg, 0.35 mmol) and water (0.5 mL, degassed). The reaction mixture was heated at 100° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C31H32ClN3O3S: 562.3 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[N:29][C:28]=1[OH:41]>C1COCC1>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:38])=[O:39])=[CH:34][CH:35]=2)[CH:30]=[N:29][C:28]=1[OH:41]
Reactant: O=S(=O)(Cl)c1ccc2c(Br)c(O)ncc2c1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)c(O)ncc3c2)cc1
Reaction time: 0.25 h

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (655 mg, 2.97 mmol) was added THF (6940 μl) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (3185 μl, 3.19 mmol), faster than drop wise. After 15 mins of stirring, a solution of 4-bromo-3-hydroxyisoquinoline-7-sulfonyl chloride (685 mg, 2.124 mmol) in THF (4 mL) was added drop wise (with 1 mL THF wash). The mixture was stirred for 1.5 hr (ice melt), LCMS indicated complete conversion to the desired product. The solution was added to ice, diluted with EtOAc and extracted with water and EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 60% EtOAc in hexane, to provide 4-bromo-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide. m/z (ESI) 506.0 (M+H)+
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=O)[CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.CCCCCC.CCOC(C)=O>[C:16]([C:15](=[C:9]1[CH2:10][C:5]2([CH2:4][CH2:3][CH2:2][CH2:1]2)[O:6][CH2:7][CH2:8]1)[C:14]([O:13][CH3:12])=[O:18])#[N:17]
Reactant: O=C1CCOC2(CCCC2)C1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(C#N)=C1CCOC2(CCCC2)C1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of 6-oxaspiro[4.5]decan-9-one (13.74 g, 89.1 mmol), methylcyanoacetate (9.4 ml, 106.9 mmol), ammonium acetate (1.79 g, 26.17 mmol) and acetic acid (1.02 ml, 17.8 mmol) in benzene (75 ml) was heated at reflux in a 250 ml round bottom flask equipped with a Dean-Stark and a reflux condenser. After 3 h, TLC (25% EtOAc in hexane, PMA stain) showed the reaction was completed. After cooling, benzene (50 ml) was added and the layer was separated, the organic was washed by water (120 ml) and the aqueous layer was extracted by CH2Cl2 (3×120 ml). The combined organic was washed with sat'd NaHCO3, brine, dried and concentrated and the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 5% EtOAc, 2 CV; 5-25%, 14 CV; 25-40%, 8 CV) gave a mixture of E and Z isomers: methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (18.37 g, 87.8% yield, m/z 236.0 [M+H]+ observed) as a clear oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1>CN(C=O)C.O.C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)=[O:11])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
ethyl 1-(1H-benzo[d]imidazole-2-carbonyl)piperidine-4-carboxylate (80 mg, 0.265 mmol) and cesium carbonate (130 mg, 0.398 mmol) were dissolved in DMF (Volume: 2.0 ml). 1-chloro-4-(chloromethyl)benzene (0.051 ml, 0.398 mmol) was added and the reaction was heated at 80° C. overnight. After 18 hours, the reaction was cooled to room temperature and diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride four times before it was dried over magnesium sulfate, filtered and concentrated. The crude material was taken directly to the next step without purification. (Yield: 85 mg, beige solid). 1H-NMR (400 MHz, DMSO-d6) 7.74, 7.66, 7.47-7.21, 5.51, 5.15, 4.48, 4.43-4.32, 4.08, 3.96-3.85, 3.16, 2.99, 2.69-2.55, 1.98-1.87, 1.76-1.66, 1.52-1.38, 1.26-1.12
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>>[C:1]1([CH:11]=[CH:12][C:13]([Cl:19])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)C=Cc1cccc2ccccc12
Yield: 99 %

Procedure:
3-(1-Naphthalenyl)-2-Propenoic acid (7.5 g, 0.038 mol) was slurried in 15 ml of oxalyl chloride and refluxed for 2 hr. The resulting solution was evaporated to yield 8.0 g (99 percent) of yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:16][CH3:17])[CH2:8][CH2:7][C:6](=O)[NH:5][CH:4]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C1COCC1>[CH3:17][O:16][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][CH2:6][NH:5][CH:4]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC1(OC)CCC(=O)NC1c1cccnc1
Solvent: C1CCOC1
Product: COC1(OC)CCCNC1c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
To 3,3-Dimethoxy-2,3,4,5-tetrahydro-1H-[2,3′]bipyridinyl-6-one (1.0 g, 421 mmol) in 3 mL THF was added borane-dimethylsulfide complex (3.0 mL, 6.0 mmol of a 2 M solution in THF) at 0° C. The solution was stirred at rt overnight, and was then quenched with methanol and heated at reflux for 2 h. The methanol was removed under vacuum and the residue was partitioned between water and chloroform. The mixture was acidified to pH=3 and washed with CHCl3 (3–10 mL). The aqueous material was then basifed to pH=8 with solid NaHCO3 and then was extracted with CHCl3 (3×15 mL). The extracts were dried over MgSO4 and concentrated to give 812 mg (86%) of a pale yellow oil: mass spectrum m/e=223.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([F:21])=[CH:11][C:10]=2[OH:22])=[C:4]([F:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:22][C:10]1[CH:11]=[C:12]([F:21])[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:14][C:9]=1[C:8](=[O:23])[NH:7][CH2:6][C:5]1[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][C:4]=1[F:26])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1ccc(Br)cc1F)c1cc(N2CCOCC2)c(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(N2CCOCC2)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-morpholin-4-yl-benzamide (0.8 g, 2.13 mmol) in acetone (11 mL), was treated with aq 2 N K2CO3 (1.6 mL, 3.20 mmol) and ethyl bromoacetate (0.35 mL, 3.20 mmol), and heated to 50° C. After stirring for 30 min, the reaction was cooled to room temperature and acidified to pH 7 with aq 2 N HCl. The resulting solution was extracted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid ethyl ester (0.8 g, 81%): 1H NMR (DMSO-d6 300 MHz) δ 9.05 (t, J=6 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.09 (ddd, J1=8.4 Hz, J2=2.4 Hz, J3=0.9 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.54 (d, J=10.2 Hz, 1H), 7.15 (d, J=14.1 Hz, 1H), 4.94 (s, 2H), 4.63 (d, J=6 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.71 (t, J=4.7 Hz, 4H), 2.92 (t, J=4.7 Hz, 4H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:14]([C:15]2(O)[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1>[Pd].CO>[C:21]1([CH:18]2[CH2:17][CH2:16][CH:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C1CCC(c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
TFA (3 ml) was added to 1-(2-aminopyridin-3-yl)-4-phenylcyclohexanol (246 mg) and the mixture was stirred at 40° C. under nitrogen for 6 hr. TFA was removed in vacuo and this product was subjected to the next reaction without further purification. MeOH (1 ml) and Pd/C (10 mg) were added and the mixture was stirred at room temperature under hydrogen for 2 days. The insoluble solid was removed by filtration through Celite-pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (38.6 mg) as colorless oil.
Reaction SMILES: [CH2:1]([C@H:3]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[CH2:4][OH:5])[CH3:2].C([OH:14])(C)C.N[C@H](C(OC)=O)CC1C=CC=CC=1.N[C@@H](C(OC)=O)CC1C=CC=CC=1>CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([C@H:3]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[C:4]([OH:14])=[O:5])[CH3:2]
Reactant: CC[C@@H](CO)CC[N+](=O)[O-]
Reactant: CC(C)O
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: COC(=O)[C@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC[C@H](CC[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To 1.0 mmol alcohol 2b dissolved in 10 mL acetone at 0° C. was added 1.5 mmol H2Cr2O7 (3 mL Jones reagent). The mixture was stirred for 5 h, during which time the mixture warmed to room temperature. Excess isopropanol was added, and the mixture was stirred for 10 min. The mixture was filtered, and the solution was diluted with 2 mL 2 N HCl and extracted with Et2O. Complete extraction of the product into the Et2O phase was monitored by TLC. The organic layers was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give a viscous oil, of which the desired product 3 was purified via column chromatography eluting with EtOAc/hexane (1:10 to 1:3; v/v) to give pure product as a yellow oil in 92% yield. TLC Rf=0.45 (EtOAc/hexanes, v/v, 1:1) 1H NMR (300 MHz, CDCl3) 4.56-4.41 (m, 2H), 2.53-2.44 (m, 1H), 2.38-2.19 (m, 2H), 1.84-1.60 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.66, 73.55, 43.57, 28.41, 25.24, 11.41. HRMS m/z (ESI): calc. for C6H11NO4Na [M+Na]+184.0586, found 184.0578. Optical rotation: [α]rtD+17.51 (c=3.82, CHCl3). The ee of this compound (>95%) was determined by coupling one portion to L-Phe-OMe and another portion to D-Phe-OMe and then analyzing the products by 1H NMR spectroscopy.