Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[O:23]([CH2:30][CH:31]=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:31][CH2:30][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CCOc1ccccc1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC1=C(CCON=CCOc2ccccc2)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with phenoxyacetaldehyde by the method of Example 1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:8])=[O:9])=[C:11]([F:30])[CH:12]=2)=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 88 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.51 g, 0.85 mmol) prepared in Example 45a, triethylsilane (0.68 mL), trifluoroacetic acid (0.85 mL) and dichloromethane (8.5 mL), to yield the title compound (333.4 mg, 88%) as a colorless solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].N.CO>O1CCCC1.O>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: NC(=O)c1cc(-c2ccc(Br)cc2)[nH]c1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
Trichloroacetyl isocyanate (60 μL, 0.50 mmol) was added dropwise to a solution of 2-amino-5-(4-bromophenyl)pyrrole-3-carboxamide (Reference compound No. 1-1, 0.17 g, 0.60 mmol) in anhydrous tetrahydrofuran (3.0 mL) at −40° C. and the mixture was stirred for 1 hour. Furthermore, ammonia solution 2.0 M in methanol (3.0 mL, 6.0 mmol) was added thereto, and the whole was stirred at room temperature for 3 days. Water (20 mL) was added to the reaction solution, then the precipitated solid was filtered off. The obtained solid was dried under reduced pressure to give the target compound (0.070 g) as a brown solid (Yield 36%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11]NCC)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O[C:24]([C:26]1C(C)=NC(NNCCCC)=[C:30]([N+]([O-])=O)[C:31]=1Cl)=O)C>>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([CH3:15])=[N:5][C:6]=1[NH:11][CH2:24][CH2:26][CH2:31][CH3:30]
Reactant: CCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]
Reactant: CCCCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]
Product: CCCCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Yield: 72 %

Procedure:
By replacing 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester in Example 1 c with 6-(1-butyl)hydrazino-4-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester, 5-amino-6-butylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester is obtained. Yield 72%, b.p. 200°-210°/0.01.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][OH:38])[C@@H:21]1[OH:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40]I>>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][O:38][CH3:40])[C@@H:21]1[OH:39])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OCCO)[C@@H]1O)(c1ccccc1)c1ccccc1
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21

Procedure:
5′-O-t-Butyldiphenylsilyl-2′-O-(hydroxyethyl)-adenosine is treated with methyliodide as per the procedure of Example 24 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH:18]([N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]1=[O:36])([CH3:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CCOC(C)=O.Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:25]2[CH:24]=[CH:23][C:22](=[O:36])[N:21]([CH:18]([CH3:20])[CH3:19])[CH:26]=2)=[N:4][C:3]=1[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: Nc1ncc(Br)nc1C#Cc1cccc(O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)n1cc(-c2cnc(N)c(C#Cc3cccc(O)c3)n2)ccc1=O
Temperature: 60 °C
Yield: 21.1 %

Procedure:
3-[2-(3-Amino-6-bromo-pyrazin-2-yl)ethynyl]phenol (100 mg, 0.3447 mmol), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (108.8 mg, 0.4136 mmol) and K3PO4 (146.3 mg, 0.6894 mmol) were combined in MeCN (2 mL)/water (0.5 mL) and Pd[P(tBu)3]2 (8.811 mg, 0.01724 mmol) was added. The reaction was heated at 60° C. for 15 hours. The reaction was cooled to ambient temperature and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (VARIAN 971-FP™, 8 g column, eluting with 0 to 10% MeOH/DCM, dry loaded) to give the title compound as a yellow solid (25.2 mg, 21% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.38 (d, 6H), 5.11 (sept, 1H), 6.49 (d, 1H), 6.77 (s, 2H), 6.87 (dd, 1H), 7.12 (s, 1H), 7.18 (d, 1H), 7.25 (t, 1H), 7.99 (dd, 1H), 8.20 (d, 1H), 8.55 (s, 1H) and 9.74 (s, 1H) ppm; MS (ES+) 347.1.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[NH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28](I)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CCOC(C)=O>[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28]([C:8]3[NH:7][C:6]4[CH:2]([CH3:1])[NH:3][C:4](=[O:19])[C:5]=4[CH:9]=3)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: CC1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 105 °C
Yield: 106 %

Procedure:
A glass microwave reaction vessel was charged with 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (472a, 500 mg, 1.91 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (681 mg, 1.91 mmol) in 1,4-dioxane (6.0 mL)/water (1.5 mL) followed by K3PO4 (1215 mg, 5.72 mmol), Xphos (91 mg, 0.191 mmol, Sigma-Aldrich) and Pd2dba3 (87 mg, 0.095 mmol, Strem). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 105° C. for 45 min. The mixture was cooled to RT and EtOAc (50 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (40 mL×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The reaction was repeated on a 1000 mg scale and the residues were combined and purified with silica gel chromatography (eluted with 1-4% MeOH in DCM) to give 2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472b, 740 mg, 36% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 366 (M+1). This material was subjected to chiral SFC to give two eluents: the first eluent was Example 450 (530 mg); the second eluent was (S)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472) (110 mg) as a tan solid. The SFC conditions were: [AS-H (Sum, 21 mm×25 cm, S/N=1071) with 45% organic modifier: 55% carbon dioxide, organic modifier: MeOH with 20 mM ammonia. Flow rate=50 mL/min]. The analytical data for (S)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472) was: MS (ESI, pos. ion) m/z: 366.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (1H, br. s.), 7.79-7.97 (2H, m), 7.61 (1H, s), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.95 (1H, s), 4.53 (1H, q, J=6.6 Hz), 3.48 (3H, s), 1.51 (9H, s), 1.37 (3H, d, J=6.7 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][OH:4].C(O)CCCCCCCCC/C=C\CC.Br[C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1.ClC1OC(C(O)=O)=CC=1>>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][O:4][C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1
Reactant: CCCCCCCCCCCCC(C)CO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC/C=C\CCCCCCCCCCO
Agent: O=C(O)c1ccc(Cl)o1
Product: CCCCCCCCCCCCC(C)COc1ccc(C(=O)O)o1

Procedure:
In the procedure of Example 4(A), 2-methyltetradecanol was substituted for cis-11-tetradecenol and 5-bromo-2-furoic acid substituted for 5-chloro-2-furoic acid to yield 5-(2-methyltetradecyloxy)-2-furancarboxylic acid, M.P. 88°-90° C.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[C:19]([C:24](=[CH:30]OCC)[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])[CH2:20][CH2:21][CH3:22]>CCOCC>[C:19]([C:24](=[CH:30][NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N:5]1[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]2[C:1]1=[O:18])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: Nc1ccccc1N1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: CCCC(=O)C(=CNc1ccccc1N1C(=O)c2ccccc2C1=O)C(=O)OCC

Procedure:
2-Phthalimidoaniline (44.0 g, 0.21 moles) and ethyl 2-butyryl-3-ethoxyacrylate (45 g, 0.21 moles) were heated together in fusion for 10 minutes then allowed to cool, forming a tan solid. The ethyl 2-buryryl-3-(2-phthalimidophenylamino)acrylate (83.0 g, 97%) was stirred in ether, filtered and dried under vacuum, m.p 153°-5° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:13][C:11]([F:12])([F:14])[CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][OH:2])[CH2:6][CH2:7]1
Reactant: COC(=O)CN1CCC(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN1CCC(C(F)(F)F)CC1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S:20][CH2:21][C@H:9]23)=[CH:4][CH:3]=1.[OH:22]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S@@:20](=[O:22])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3CSC[C@@H]32)cc1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=[S@]1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 81.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (20 mg, 0.066 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at room temperature for 30 minutes. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ4-thia-cyclopenta[a]naphthalen-8-ol 13 (17 mg, 0.054 mmol, 85%). 1H NMR (δ, 400 MHz, MeOD) 7.44 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.70 (d, 1H, J=2.8 Hz), 6.61 (dd, 1H, J=8.8, 2.8 Hz), 5.19 (s, 1H), 4.19 (dd, 1H, J=6.2, 6.2 Hz), 3.76 (d, 1H, J=7.9 Hz), 3.06-2.94 (m, 1H), 2.84 (dd, 1H, J=14.1, 5.3 Hz), 2.62 (dd, 1H, J=13.0, 5.5 Hz), 2.29 (dt, 1H, J=5.2, 14.0 Hz). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.17 min). LRMS calcd for C17H15O4S: 315.1; found (ES−, M−H): 315.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C>[N:20]1([CH2:2][CH2:3][CH2:4][C:5]23[CH2:19][CH:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=42)[C:11]2[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: ClCCCC12CC(c3ccccc31)c1ccccc12
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)C1CC2(CCCN2CCCCC2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of 9-γ-chloropropyl-9,10-dihydro-9,10-methanoanthracene (50 mg) and piperidine (0.1 ml) was heated at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-piperidinopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted into its hydrochloride. M.P. 280°-283° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[O:24][CH3:25])=[CH:5][CH:4]=1>[Pd].C(O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[O:24][CH3:25])=[CH:27][CH:28]=1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Yield: 80.2 %

Procedure:
N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzamide (500 mg) was suspended into ethanol (70 ml) and hydrogenated with 10% palladium/carbon (500 mg) at room temperature under a hydrogen pressure of 3.0 kg/cm2. The reaction liquor was filtered and concentrated and the residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:methanol=50:1) to obtain 403 mg (80%) of aimed compound as crystals. Further, these were recrystallized from ethyl acetate to obtain purified aimed compound as colorless powdery crystals. Melting point 176.0~177.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CC(C)C(=O)c1ccc(OCCCBr)cc1

Procedure:
The mixture of the phenol from Step A (4.0 g) 1,3-dibromopropane (18.2 ml), potassium carbonate (7.5 g) and methyl ethyl ketone (100 ml) was refluxed for 1 hour. The mixture was filtered, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the title compound as an oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:15](=[O:22])[N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[CH3:21]
Reactant: CCOC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)N1CCNCC1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
HCl (8 mL) was added to a stirred solution of 4-(2-ethoxycarbonyl-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (5 g, 17 mmol) in dioxane (5.0 mL) at 0° C. and the resulting mixture stirred for 30 minutes. The mixture was then concentrated and the residue was washed with diethyl ether and dried to afford 4.1 g (82%) of 3-oxo-3-piperazin-1-yl-propionic acid ethyl ester hydrochloride. LCMS: 237.1 (M+1)+ 82%
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:21][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNC3CCCC3)cc2)cc1
Reaction time: 48 h
Yield: 82.3 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.1 mmol) and cyclopentylamine (2.5 g, 25 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (1.57 g, 25.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 5.5 g (83%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.31-1.45 (m, 2H), 1.49-1.65 (m, 2H), 1.65-1.80 (m, 3H), 1.81-1.95 (m, 2H), 3.15 (p, J=7.5 Hz, 1H), 3.75 (s, 2H), 6.94-7.04 (m, 4H), 7.05-7.14 (m, 1H), 7.25-7.40 (m, 4H). MS (DCl/NH3) m/e 268 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[O:23]>CC(O)C.CCOC(C)=O>[Br:16][C:17]1[C:18]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=1)=[O:23]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
(R)-Pyrrolidin-3-ol (17.1 ml, 211.2 mmol) and DIPEA (67.6 ml, 387.6 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.3, 69.6 g, 175.9 mmol) in iPrOH (120 mL) and stirred at 140° C. for 1 h. The mixture was diluted with EtOAc (1 L), washed with 1N HCl (2×200 mL), a sat. solution of NaHCO3 (200 mL) and brine (2×200 mL) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/iPr2O to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR=6.58 min, UPLC-MS (Condition 6) m/z=446.0/448.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.76 (m, 1H) 3.79-3.91 (m, 2H) 4.33 (br. s, 1H) 4.97 (d, J=3.13 Hz, 1H) 7.33 (d, J=9.38 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.30-8.36 (m, 1H) 8.66 (d, J=2.35 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14].[Cl:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.Cl>COCCO.O>[Cl:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[OH:14])=[O:22])=[CH:19][CH:18]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Cc1ccc(O)c(NC(=O)c2ccc(CCl)cc2)c1

Procedure:
With stirring, 37.52 g (446.6 mmol) of sodium bicarbonate were added to 50 g (406 mmol) of 2-amino-4-methylphenol in 250 ml of 2-methoxyethanol. 84.4 g (446.6 mmol) of 4-chloromethylbenzoyl chloride, dissolved in 250 ml of 2-methoxyethanol, were then added dropwise to the solution over 15 min. During this time, an increase in reaction temperature of from room temperature to 40° C. was observed. After 4 hours of stirring, 1 liter of water and 10 ml of concentrated hydrochloric acid were added to the reaction mixture. The crystals formed were filtered off and dried under reduced pressure. This gave 116 g of the target compound which were reacted further without further purification.