Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C@H:46]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[CH2:47][C:48]1([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]1>C(Cl)Cl>[C:58]1([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:57]=[CH:56][C:55]([CH2:54][C@@H:46]([NH:45][C:6]([C:5]2[CH:4]=[C:3]([C:9]([OH:11])=[O:10])[NH:2][N:1]=2)=[O:8])[CH2:47][C:48]2([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]2)=[CH:60][CH:59]=1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1)c1cc(C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
3,5-Pyrazoledicarboxylic acid (35.2 mg, 226 μmol, 1.0 eq.), DIPEA (126 μL) and HATU (85.9 mg, 226 μmol, 1.0 eq.) and DCM (5 mL) were combined and stirred for 5 minutes at room temperature. 1-((R)-2-Amino-3-biphenyl-4-yl-propyl) -cyclopropanecarboxylic acid (86.7 mg, 294 μmol, 2.3 eq,) and DIPEA (0.5 mL) in DCM (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and the product was extracted with DCM, dried and evaporated. The resulting product was combined with AcOH (1.5 mL) and purified with preparative HPLC to yield the title compound (21.4 mg; 93% purity). MS m/z [M+H]+ calc'd for C24H23N3O5, 434.16; Found 433.5.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:3]2[CH:2]=[C:1]([NH:17][C:14]3[CH:13]=[C:12]([CH3:11])[NH:16][N:15]=3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Nc1ccc(F)cc1
Reactant: N#CC=Cc1ccccc1
Product: Cc1cc(Nc2cc(Nc3ccc(F)cc3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 86 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and 4-fluoroaniline. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:17][CH2:18][C:19]([N:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[C:39]([CH3:42])[CH:38]=[C:37]3[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C:24]=1[Cl:51])[CH3:22])=[O:20].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:51][C:24]1[C:25]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[C:39]([CH3:42])[CH:38]=[C:37]3[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][C:14](=[O:16])[CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Nc1ccc(CCC(=O)O)cc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCc4ccc(NS(C)(=O)=O)cc4)c3Cl)c2n1

Procedure:
Compound 29 was prepared from 3-(4-(methylsulfonamido)phenyl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methyl-4-(pyridin-2-ylmethoxy)quinolin-8-yl)oxy)methyl)phenyl)-N-methylacetamide in a as described for compound 1. MS (APCI) 736 (M+), 1H NMR (CDCl3) 2.45-2.56 (m, 2H), 2.65 (s, 3H), 2.83-2.92 (m, 5H), 3.15 (s, 3H), 3.35-3.48 (m, 1H), 3.75-3.85 (m, 1H), 5.41 (s, 2H), 5.61 (s, 2H), 6.61-6.65 (m, 1H), 6.71 (s, 1H), 7.15 (s, 4H), 7.24-7.34 (m, 2H), 7.3-7.45 (m, 5H), 7.56-7.61 (d, 1H, J=7.8 Hz), 7.66-7.78 (m, 1H), 7.91-7.94 (dd, 1H, J=1, 7.74 Hz), 8.64 (d, 1H, J=4.14 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(#N)C.Br[C@H:22]([CH3:37])[C:23]([N:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24]>ClCCl>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:22]([CH3:37])[C:23]([N:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
Introduce into a reactor 105 g of ethyl (2S)-2-aminopentanoate, 135 ml of triethylamine and 135 ml of acetonitrile, and then bring the mixture to 60° C. and slowly add a solution of 200 g of the compound obtained in Step A in 1.3 liters of dichloromethane, and subsequently reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield (2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}octahydro-1H-indole-2-carboxylic acid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14]>ClCCl>[C:5]1([CH:6]2[S:15][CH2:11][CH2:12][CH2:13][S:14]2)[CH:8]=[CH:9][C:2]([CH:1]2[S:15][CH2:11][CH2:12][CH2:13][S:14]2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: SCCCS
Solvent: ClCCl
Product: c1cc(C2SCCCS2)ccc1C1SCCCS1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
In a three-neck flask, 100 ml in inner volume, made of glass and provided with a stirrer, 4.0 g (30 mmols) of terephthal aldehyde and 30 g of dichloromethane were placed. The reactants, after having added 8.1 g (75 mmols) of 1,3-propane dithiol, were stirred continuously at 25° C. for 20 minutes and, after having subsequently added 6.3 ml (50 mmols) of a boron trifluoride diethyl ether complex, further stirred continuously at 25° C. for two hours, to form a white precipitate. The resultant white precipitate was filtered, to obtain 6.6 g (70% in yield) of 2,2′-(1,4-phenylene) bis-1,3-dithian (hereinafter referred to as “Intermediate (3)”).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][S:15]SC>N1C=CC=CC=1>[CH2:12]([O:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([S:15][CH3:14])[C:9]=1[OH:10])[CH:5]=[O:6])[CH3:13]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: CSSC
Solvent: c1ccncc1
Product: CCOc1cc(C=O)cc(SC)c1O
Temperature: 90 °C
Yield: 69.3 %

Procedure:
To the solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.00 g, 4.08 mmol) in pyridine (10 mL) was added Cu powder (0.52 g, 8.1 mmol) and methyl disulfide (0.77 g, 8.2 mmol), the mixture was then heated at 90° C. overnight. The reaction mixture was filtered, and the solvent was removed under reduced pressure, the residue was poured into water, and 6 N HCl (5 mL) was added, then the mixture was extracted with DCM (50 mL×3), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE:EA=5:1) to give Intermediate 50 (600 mg, yield 69%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:12][C:11]3=[N:13][CH:14]=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[N:4]1)[CH3:2].CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:12][C:11]3=[N:13][CH:14]=[C:15]([C:25]4[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=4)[N:10]3[N:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2nn3c(I)cnc3s2)cn1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)cn1
Yield: 13.2 %

Procedure:
A mixture of 2-(1-Ethyl-1H-pyrazol-4-yl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (110 mg, 0.319 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (119 mg, 0.414 mmol, 1.3 eq), Pd(PPh3)2Cl2 (45 mg, 0.064 mmol, 0.2 eq) and 2M aq Na2CO3 (1 mL) in dioxane (3 mL) was refluxed for 2 h. The solvent was evaporated and the residue was treated with water. The suspension was filtered off and washed with Et2O. The solid was purified by column chromatography (DCM/MeOH 9:1) to afford the desired product (16 mg, 13%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.62 min, [M+H]+ m/z 380.1; 1H NMR (300 MHz, DMSO) δ 8.84 (s, 1H), 8.61 (s, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 6.72 (s, 2H), 4.24 (q, J=7.3 Hz, 2H), 1.43 (t, J=7.3 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14](=[O:28])[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[Cl:29].[OH-].[Li+]>CO.O.O1CCCC1>[Cl:29][C:7]1[C:8]([CH2:12][O:13][C:14](=[O:28])[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 76.1 %

Procedure:
{2-Chloro-3-[(diphenylcarbamoyloxy)methyl]phenoxy}acetic acid methyl ester (0.64 g, 1.5 mmol) was dissolved in a mixture of methanol (20 mL), water (5 mL), and tetrahydrofuran (2 mL). An aqueous solution of lithium hydroxide (0.07 g, 1.65 mmol) was added and the mixture was allowed to stir overnight. The mixture was concentrated in vacuo, and the residue diluted with water and washed with diethyl ether. The aqueous layer was acidified with 3M hydrochloric acid forming a white precipitate which was filtered and dried. Recrystallization from methanol gave {2-chloro-3-[(diphenylcarbamoyloxy)methyl]phenoxy}acetic acid as white needles (0.47 g, 76.5%); m.p. 182.2-182.9° C.; 1H NMR 4.66 (s, 2H), 5.30 (s, 2H), 6.83 (dt, J=7.5Hz, 2H), 7.11 (t, J=8.0Hz), 7.28 (m, 10H); 13C NMR 64.98 (t), 66.02 (t), 112.96 (d), 121.62 (d), 126.27 (d), 126.93 (d), 127.02 (d), 128.94 (d), 135.79 (s), 142.34 (s), 153.68 (s), 154.27 (s), 170.26 (s). Analysis for C22H18ClNO5: Calcd.: C, 64.16; H, 4.41; N, 3.40. Found: C, 64.30; H, 4.39; N, 3.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][C:4]=1[CH:14]=[O:15]
Reactant: COc1ccc(-c2csnn2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2csnn2)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.99 grams (5.15 mmol) of 4-(4-methoxyphenyl)-1,2,3-thiadiazole (Maybridge Chemical Co.) in 23 mL of anhydrous methylene chloride (Ch2Cl2) cooled to 0° C., was treated with 2.3 mL (21.9 mmol) of titanium tetrachloride and stirred for 30 min. The red solution was treated with 0.97 mL (10.7 mmol) of α,α-dichloromethyl methyl ether and allowed to warm to room temperature overnight. The reaction mixture was then poured over 100 mL of saturated aqueous sodium bicarbonate (NaHCO3), the pH was adjusted to 7-8 with solid NaHCO3 and the solution was then extracted with CH2Cl2. The organic layer was dried with magnesium sulfate (MgSO4) and concentrated to a yellow solid. Chromatography on silica gel (20% EtOAc: 80% Hexane) gave the pure title compound as a light yellow solid, 0.35 g (31%).
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:13][O:12][C:8]1[C:9]([O:10][CH3:11])=[CH:2][C:3]([CH:4]=[O:5])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1ccc(C=O)c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C=O)c(-c2ccc(SC)cc2)cc1OC
Temperature: 25 °C
Yield: 71.5 %

Procedure:
2-Bromoveratraldehyde (25 g, 103.3 mmol) and 4-(methylthio)benzeneboronic acid (19.66 g, 118.5 mmol) were dissolved in toluene (550 mL) and sodium carbonate (2M, 103 μL, 206 mmol) was added. To this reaction mixture was added ethanol (50 mL) followed by tetrakis (triphenylphosphine)palladium (3.4 g, 2.5 mmol) and the reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (250 mL) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were washed with water (4×250 mL), brine (1×250 mL), dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give the crude product. The product was purified by trituration with ethyl acetate/hexane to give the title compound as a white solid (21.3 g, 85% yield), mp 114-115° C. 1H NMR (CDCl3, 300 MHz) δ 9.83 (s, 1H), 7.64 (s, 1H), 7.43-7.23 (m, 4H), 6.83 (s, 1H), 3.98 (d, J=2.4 Hz, 6H), 2.55 (s, 3H). 13C NMR (CDCl3, 75.45 MHz) δ 190.9, 153.4, 148.7, 1408, 138.9, 134.5, 134.1, 130.5, 130.1, 128.0, 128.0, 126.9, 126.1, 112.5, 108.7, 56.2, 56.1, 15.6. LRMS (APIMS) m/z 289 (M+H)+.
Reaction SMILES: O.[OH:2][CH2:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[O:2]=[CH:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Water (2.57 ml, 143 mmol) was added dropwise to a mixture of (R)-tert-butyl (1-hydroxypropan-2-yl)carbamate (17.85 g, 102 mmol) and Dess-Martin Periodinane (60.5 g, 143 mmol) in anhydrous DCM (500 ml) at rt under a nitrogen atmosphere. The reaction was allowed to stir at rt overnight before diluting with diethyl ether and filtering. The filtrate was evaporated in vacuo and the residue diluted with diethyl ether. The organic was then washed with a 1:1 mixture of 10% aq sodium thiosulfate solution: sat. sodium bicarbonate solution, followed by brine and water. The aqueous phase was then back extracted with one portion of diethyl ether, the combined organics were then dried (MgSO4) and evaporated in vacuo to give (R)-tert-butyl (1-oxopropan-2-yl)carbamate (15 g, 87 mmol, 85% yield) as a white solid.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C@H:5]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[C@:6]3([CH2:8][CH2:9][C@H:10]4[C@H:19]([C@@:2]123)[CH2:18][CH2:17][C@H:16]1[C@:11]4([CH3:21])[CH2:12][CH2:13][C:14](=[O:20])[CH2:15]1)[CH3:7].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[H-].O>O1CCCC1>[O:24]1[CH:25]=[CH:26][C:22]([C@H:5]2[CH2:4][C@H:3]3[O:1][C@@:2]43[C@H:19]3[C@H:10]([CH2:9][CH2:8][C@:6]24[CH3:7])[C@:11]2([CH3:21])[C@@H:16]([CH2:15][C@H:14]([OH:20])[CH2:13][CH2:12]2)[CH2:17][CH2:18]3)=[CH:23]1
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
To a solution of 4.5 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-one in 30 ml of dry tetrahydrofuran at -78° C., a solution of 9.8 g of tri-tert-butoxyaluminum-hydride in tetrahydrofuran was added dropwise. The mixture was stirred for 20 hrs, then 40 ml of water were added and the temperature raised to 25° C. The aluminum salts were filtered on a celite cake and washed with methanol. The solution was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 4.3 g of the title compound (II-b) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:22]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Reactant: OO
Product: CCOC(=O)N1CCc2c(C)c3ccccc3[n+]([O-])c2CC1
Yield: 66 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester 6-oxide was prepared analogous to Example 111 from 1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][C:12](=[O:31])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]34[CH2:30]C5CC(CC(C5)[CH2:22]3)[CH2:28]4)=[CH:17][CH:16]=2)[CH:5]=1.[OH-].[K+].Cl>O1CCOCC1.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([NH:11][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[OH:10])[C:3]([OH:32])=[O:2])=[O:31])=[CH:16][CH:17]=1)([CH3:30])([CH3:22])[CH3:28]
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cc(C(=O)O)ccc2O)cc1
Yield: 91.9 %

Procedure:
A 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (151.8 mg, 0.35 mmol) in 1,4-dioxane/H2O (10 ml) was treated with KOH (290.7 mg, 5.18 mmol) at 60° C. for 3 h. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=4:1) to give 3-[2-(4-tert-butyl-phenoxy)acetylamino]-4-hydroxy-benzoic acid as a white solid (110.4 mg, 75.10% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:7][C:6]=1[F:22])(=O)C.C(N)C1C=CC=CC=1>C(O)C.CCOCC>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:7][C:6]=1[F:22]
Reactant: CCCCCCC(C)OC(=O)c1ccc(OC(C)=O)c(F)c1
Solvent: CCO
Solvent: NCc1ccccc1
Solvent: CCOCC
Product: CCCCCCC(C)OC(=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
The above compound (3) (1.1 g) was dissolved in 30 ml of ethanol, and 3 g of benzylamine was added dropwise. The mixture was stirred at room temperature for 24 hours, then diluted with 300 ml of ether, washed with dilute hydrochloric acid and water in this sequence, and dried over magnesium sulfate. After the solvent was evaporated, the solid was purified by silica gel column chromatograhy to afford 0.6 g of a final product (4).
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:29]1[CH:34]=[CH:33][C:32]([CH:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH3:36])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[N:37]1([CH:35]([C:32]2[CH:33]=[CH:34][C:29]([NH2:6])=[CH:30][CH:31]=2)[CH3:36])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(c1ccc(Br)cc1)N1CCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(c1ccc(N)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
LiHMDS (1 mL, 1 M solution in THF, 1.0 mmol) is added to a 25 mL round bottom flask, THF is removed. Toluene (4 mL) is added followed by addition of Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and P(tBu)3 (10 mg, 0.05 mmol). The mixture is degassed. 1-[1-(4-Bromo-phenyl)-ethyl]-pyrrolidine (330 mg, 1.3 mmol) in toluene (2 mL) is added to the flask. The resulting mixture is stirred at room temperature overnight. TLC is used to determine complete consumption of starting bromide, the reaction mixture is diluted with ether at this point and poured into dilute HCl (aq). The ether layer is discarded, the aqueous layer is basified with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer is dried and concentrated. The residue is subjected to chromatography to provide the desired product 4-(1-Pyrrolidin-1-yl-ethyl)-phenylamine (60 mg, 24%). 1H NMR (300 MHz, CDCl3) ∂ 7.09-7.13(2H, m), 6.61-6.66 (2H, m), 3.47 (2H, br), 3.11 (1H, q, J=6.6 Hz), 2.52-2.58 (2H, m), 2.33-2.39 (2H, m), 1.73-1.79 (4H, m), 1.38 (3H, d, J=6.9 Hz). MS (ESI): 191 (M+1)+1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1C=O.[F:14][C:15]([F:24])([F:23])/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:25]([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[F:14][C:15]([F:23])([F:24])[C:16]1[CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A mixture of 2-hydroxy-1-naphthaldehyde (8.6 g, 0.050 mol) and ethyl 4,4,4-trifluorocrotonate (9.2 g, 0.055 mol) dissolved in anhydrous dimethylformamide (DMF) and treated with anhydrous K2CO3 (13.8 g, 0.100 mol). The solution was maintained at room temperature for 50 hours and diluted with water. The solution was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 4.8 g of an oil. The oil was purified by HPLC, eluting with hexanes:ethyl acetate (30:1). The appropriate fractions were concentrated to afford 1.6 g (10%) of the napthopyran ester as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]=[CH2:8])(=[O:3])[CH3:2].[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=C.[C:18]1(C)C=CC=CC=1>C1(C=CC(O)=CC=1)O>[CH2:5]([O:4][C:1]([CH:2]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]1[O:13][C:9](=[O:12])[CH3:10])=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: C=CC=COC(C)=O
Reactant: Cc1ccccc1
Reactant: C=CC(=O)OCCCC
Agent: Oc1ccc(O)cc1
Product: CCCCOC(=O)C1CCC=CC1OC(C)=O
Temperature: 120 °C
Reaction time: 68 h

Procedure:
1-Acetoxy-1,3-butadiene (30.1 g, 0.268 mol) was dissolved in toluene (20 mL). To this was added butyl acrylate (37.9 mL, 0.265 mol) and hydroquinone (0.14 g). The colourless solution was heated at 120° C. for 26 h under argon. More 1-acetoxy-1,3-butadiene (10.6 g, 0.095 mol) in toluene (2 mL) was then added, and heating continued for a further 68 h. The solution was cooled then evaporated in vacuo to give a viscous yellow oil (69 g), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18](Cl)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(-c3cccc(F)c3)n2)c1

Procedure:
The chloro thiazole (114) (80 mg, 0.24 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E, except that the reaction mixture was heated for a total of 12 h. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.