Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].F[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>>[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[N+:20]([C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=1[O:8][C:1]1[CH:6]=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[CH:3][C:2]=1[N+:20]([O-:22])=[O:21])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: OCC#CC#CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Reaction of 2,4-hexadiyne-1,6-diol (1 g) with 4-fluoro-3-nitro-benzotrifluoride (4 g.) following the procedure of Example 3 yielded the desired product. Recrystallization from ethanol gave pale yellow needles. (1.1 g., 25%) m.p. 137° C. I.R. (KBr): 1620(NO2), 1120 682 (CF3)cm-1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[CH2:25][CH2:24]3)=[O:19])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(C2CCC(CC(=O)O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C2CCC(CC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)CC2)cc1
Reaction time: 12 h
Yield: 58.3 %

Procedure:
[4-(4-Acetylphenyl)cyclohexyl]acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (2.5 g) were suspended in DMF (50 mL), and triethylamine (2.1 mL), EDC hydrochloride (1.6 g) and HOBt (1.3 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (2.2 g) as a white solid. melting point: 168° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][C:29](N=C(N(C)C)N(C)C)([CH3:31])[CH3:30].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=3)[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(3,5-dimethyl-2-pyridinyl)benzenesulfonamide (56 mg, 0.145 mmol) in acetonitrile (1 mL) was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (25 mg, 0.145 mmol) and the mixture was stirred at room temperature for 1 hour, 1-bromo-2-methylpropane (0.031 mL, 0.289 mmol) was then added and the mixture was stirred at 70° C. for 125 hours. The mixture was concentrated in vacuo and partitioned between dichloromethane (5 mL) and water (5 mL). The organic layer was then purified by mass directed autoprep (formic acid modifier) to give the title compound (30 mg) as a white solid. LCMS (2 min, formic) Rt 1.31 min, m/z (ES+) 444 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.C([O-])([O-])=O.[Na+].[Na+].[OH:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[C:48]([C:55]([F:58])([F:57])[F:56])[CH:47]=1>COCCOC.O.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]>[NH2:30][C:29]1[S:28][C:27]([C:49]2[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][C:48]=2[C:55]([F:56])([F:57])[F:58])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)c1ccc(O)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(O)cc3C(F)(F)F)sc2N)c1N1CCC(CN)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
A mixture of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.123 g, 0.20 mmol), Na2CO3 (42 mg, 0.40 mmol) and 4-hydroxy-2-(trifluoromethyl)benzeneboronic acid (66 mg, 0.32 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg, 0.02 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 40 min. The solvents were removed under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a solution of HCl in 1,4-dioxane (4 M, 2 mL) and stirred at room temperature for 16 hr. The solvent was removed under reduced pressure and the residue purified by preparative HPLC to yield 278 as a pale brown solid (48 mg, 48%). 1H NMR (400 MHz, d4-MeOD) δ 7.59 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 6.98 (dd, J=8.5, 2.5 Hz, 1H), 3.72 (s, 3H), 3.22-3.10 (m, 4H), 2.71 (d, J=6.8 Hz, 2H), 1.85 (d, J=12.6 Hz, 2H), 1.66-1.55 (m, 1H), 1.47-1.33 (m, 2H). LCMS (ES+) m/z 496 (M+1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.C(O)C[OH:32]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][OH:32])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: OCCO
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CN(Cc1cccs1)C1=C(C(=O)OCCO)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 108, ethylene glycol (0.20 mL, 3.6 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0061 g, y. 10%).
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:15][O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cccc([N+](=O)[O-])c1OC
Temperature: 45 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-hydroxy-3-nitrobenzoate (26.8 g, 136 mmol) in DMF (200 mL) was added K2CO3 (61 g, 440 mmol). Then iodomethane (62 g, 436 mmol) was added dropwise to the mixture at rt. The mixture was stirred at 45° C. for 5 h. Then the mixture was cooled to rt and water was added. The reaction mixture was extracted with EtOAc (500 mL×2). The combined organic layers were washed with water successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step B (28.4 g, 98.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (dd, J=1.8 Hz, 8.4 Hz, 1H), 8.00 (dd, J=1.3 Hz, 8.2 Hz, 1H), 7.40 (dd, J=8.2 Hz, 8.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[C:8]2=[O:12])=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(OCCCCCCBr)cc1
Reactant: O=C1NCCN1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2ccc(C(F)(F)F)cc2)CCN1c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-(4-pyridyl)-2-imidazolidinone (0.10 g, 0.61 mmol) and sodium hydride (75% dispersion in mineral oil, 0.02 g, 0.67 mmol) in anhydrous DMF (7 mL) was cooled in an ice bath and stirred at 0° C. for 30 minutes, followed by addition of a solution of 1-bromo-6-[4-(trifluoromethyl)-phenoxy]hexane (0.20 g, 0.61 mmol) in anhydrous DMF (3 mL). After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution followed by extraction with a mixture of diethyl ether and ethyl acetate (3:1, 100 mL×3). The organic layers were combined and washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture thus obtained was purified with gradient chromatography [100% ethyl acetate, and, subsequently, a mixture of ethyl acetate and methanol (4:1)] to yield the product (i.e., Compound 1) as a white solid (0.18 g, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:12]=[O:13]>N1C=CC=CC=1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:11])([CH2:12][OH:13])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CC(C#N)c1ccc(Br)cc1
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CC(C#N)(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-propionitrile (27 g, 128.5 mmol) in pyridine (225 mL) was added paraformaldehyde (15.7 g, 514.3 mmol) and a 40% Triton-B solution (in methanol) (14.4 mL). Then the reaction mixture stirred at room temperature for 16 h. At this time, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with a 2N aqueous hydrochloric acid solution (2×200 mL), water (2×100 mL), sodium bicarbonate (2×50 mL), a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Flash chromatography afforded 2-(4-bromo-phenyl)-3-hydroxy-2-methyl-propionitrile as colorless oil (25.9 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Cl)c2)c1C

Procedure:
m-Chloroaniline (5 mmol, 0.6 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. Upon completion of the reaction, the crude solid was recrystallized from ethanol to afford the desired product (m.p. 99.6° C.-100.5° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([O:10][CH3:11])[CH2:8][C@@H:7]([NH2:12])[C@@H:6]([NH2:13])[CH2:5]1.Cl.CO[C@@H]1[C@H](OC)C[C@@H](N)[C@@H](N)C1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:44](OC1C=CC([N+]([O-])=O)=CC=1)=[O:45])=[CH:38]2>CN(C)C=O>[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:44]([NH:12][C@@H:7]1[CH2:8][C@H:9]([O:10][CH3:11])[C@H:4]([O:3][CH3:2])[CH2:5][C@@H:6]1[NH2:13])=[O:45])=[CH:38]2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cc2cc(Cl)ccc2[nH]1
Reactant: CO[C@H]1C[C@@H](N)[C@@H](N)C[C@H]1OC
Agent: CO[C@H]1C[C@H](N)[C@H](N)C[C@H]1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C[C@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture (645 mg) of (1R*,2S*,4R*,5S*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride and (1R*,2S*,4S*,5R*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride was suspended in N,N-dimethylformamide (50 ml), and triethylamine (1.10 ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (920 mg) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with dichloromethane. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:9) to obtain a mixture (330 mg) of (1R*,2S*,4R*,5S*)-N1-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamine and (1R*,2S*,4S*,5R*)-N1-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamine as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C@H:6]([C:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][C:32](=[O:34])[CH3:33])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH2:13]3)[CH2:10][CH:9]=1)[CH3:7].[H][H]>C(O)C.[Pt]>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][C:32](=[O:34])[CH3:33])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: [H][H]
Reactant: COC(=O)CC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pt]
Solvent: CCO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98.5 %

Procedure:
To a solution of 8.8 g of 1α,3β-diacetyloxychola-5,16-dien-24-oic acid methyl ester in 200 ml of absolute ethanol was added, under a nitrogen atmosphere, 0.8 g of 5% platinum on charcoal. The suspension was then stirred under a hydrogen atmosphere at 23° C. until hydrogen absorption ceased (2.75 h; 423 ml; theory, 437 ml). Filtration through diatomaceous earth did not remove all colloidal particles. The evaporated filtrate was dissolved in 50 ml of ethyl acetate--methylene chloride (1:1) and was then percolated through a column of 20 g of silica gel using the same solvent mixture. Evaporation of the solvents gave 8.7 g (99%) of 1α,3β-diacetyloxychol-5-en-24-oic acid methyl ester as a white solid, mp 108°-113° C. An analytical sample, recrystallized from methanol, had mp 110.5°-112° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:61]C1C=C(N=C=S)C=CC=1>>[Cl:61][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: S=C=Nc1cccc(Cl)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O

Procedure:
The compound of example 63 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 3-chlorophenyl isothiocyanate. The compound of example 63 was used directly without isolation for the preparation of compound of example 64.
Reaction SMILES: O[CH:2]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1.[ClH:29]>ClCCl.O.C(=O)(O)[O-].[Na+]>[Cl:29][CH:2]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1
Reactant: N#Cc1cccc(C(O)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(C(Cl)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1

Procedure:
A suspension of the 3-[α-hydroxy-3-{2(E)-(quinolin-2-yl)ethenyl}benzyl]benzonitrile (1.4 g, 3.87 mmol) in dichloromethane (75 ml) was stirred with concentrated hydrochloric acid (75 ml) for 3 hours, diluted with water and neutralised with saturated sodium bicarbonate solution. The aqueous layer was extracted with further dichloromethane and the combined solvent was dried and evaporated to a pale solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:31])[C:21]=1[N:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[N:23]1)[O:5][CH:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].Cl.[NH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>[Cl-].[NH4+].CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:31])[C:21]=1[N:22]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[N:23]1)[O:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:16])=[CH:17][CH:18]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 4 h
Yield: 78.6 %

Procedure:
N,N-dimethylformamide (1.88 mL) was added to a vial containing 4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (122.0 mg, 0.28 mmol), ethyl 3-aminopropanoate hydrochloride (86.6 mg, 0.56 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (214.0 mg, 0.56 mmol). Diisopropylethylamine (0.25 mL, 1.41 mmol) was then added. After stirring for 4 hours, the reaction was diluted with saturated ammonium chloride and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-25% ethyl acetate in heptane) afforded (+/−)-ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (117 mg, 78% yield). 1H NMR (400 MHz, CDCl3, δ): 7.87 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J=8.2 Hz, 2H), 6.84 (d, J=5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J=7.8, 5.1 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.71 (q, J=6.0 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.04-1.91 (m, 1H), 1.88 (s, 6H), 1.86-1.71 (m, 1H), 1.58-1.33 (m, 2H), 1.26 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 532.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([Sn](CCCC)(CCCC)[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC>O1CCOCC1>[F:27][C:22]1[C:21]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:48]5[N:53]=[CH:52][CH:51]=[CH:50][N:49]=5)[CH:3]=4)[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(-c3ncccn3)cc12
Temperature: 100 °C
Yield: 11.7 %

Procedure:
A vial was charged with (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (100 mg, 0.23 mmol), AmPhos (15.97 mg, 0.023 mmol), 2-(tributylstannyl)pyrimidine (333 mg, 0.90 mmol) and dioxane (1.50 mL). The vial was purged with Ar (g), sealed, and heated to 100° C. overnight. After cooling to rt, crude was diluted with MeOH (3 mL) and purified with reverse phase HPLC. Fractions containing product were washed with saturated aq. NaHCO3 (15 mL) and extracted with ethyl acetate (1×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a white solid, (S)-7-(2-fluoropyridin-3-yl)-3-(pyrimidin-2-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (12 mg, 0.027 mmol, 12% yield). MS m/z=443.0 [M+H]+. Calc'd for C23H15FN6OS: 442.47.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(N)c1NCCCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Under hydrogen gas atmosphere, a mixture of 5-[(2,6-dinitrophenyl)amino]pentan-1-ol (Reference Example 109; 1.30 g, 4.82 mmol), 10% palladium on carbon (50% wet, 260 mg) and tetrahydrofuran (48 mL) was stirred at room temperature for 2 hr. The reaction mixture was filtered and concentrated in vacuo to give the title compound as an oil (873 mg, 4.17 mmol, 86%).
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH2:37][CH3:38])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:36]>>[CH2:37]([C:24]12[C:25](=[O:36])[CH:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][C:33]=31)[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH3:38]
Reactant: CCC1(CCCCCl)C(=O)CCc2ccc(OC)cc21
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Product: CCC12CCCCC(Cc3ccc(OC)cc31)C2=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl- 5,10 methano-5H-benzocyclononen-12-one there is obtained from 37.4 g. of 1-(4-chlorobutyl)-1-ethyl-7-methoxy-2-tetralone, 22.2 g. of the title product, b.p. 138° to 142° C. (0.35 mm.).