Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=1[NH2:10]>Cl.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:9]=1[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: COc1ccc(Cl)c(N)c1
Reactant: C/C=C/C=O
Agent: Cl
Solvent: O
Product: Cc1ccc2c(O)ccc(Cl)c2n1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Crotonaldehyde (17.5 mL, 0.21 mol) was added dropwise to a refluxing solution of 2-chloro-5-methoxyaniline hydrochloride (10.36 g. 53.4 mmol) in 5 N hydrochloric acid (450 mL) and reflux continued for a further 0.5 h. The reaction mixture was cooled and diluted with water (500 mL), then extracted with ether (400 mL). The aqueous layer was separated and basified using 50% aqueous NaOH (pH 14), and then extracted into dichloromethane (3×300 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜200 g) eluting with 20% EtOAc in hexane to give a brown oil (5.17 g) which was heated at reflux in a mixture of acetic acid (30 mL) and 48% hydrobromic acid (30 mL) for 66 h. Reaction mixture was evaporated in vacuo and the residue suspended in sat. NaHCO3 (aq), then extracted into dichloromethane (3×50 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a brown solid (2.90 g, 28%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=O)(C)(C)C>Cl.C(O)C>[NH2:8][CH:9]([CH:17]([OH:24])[CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)CC(O)C(O)C(N)CC1CCCCC1

Procedure:
(2S,3R,4S)-2-[(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (5.05 g, 14.7 mmol, Luly et al., J. Org. Chem. 1988, 53, 6109) was stirred for 90 min in 4M hydrochloric acid in ethanol and then evaporated. Ether was added and evaporated 3 times and the residue was dried under high vacuum. The title compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:34])[CH2:32][CH2:31][N:30]([NH2:33])[CH2:29][CH2:28]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:33][N:30]3[CH2:31][CH2:32][C:27]([F:34])([F:26])[CH2:28][CH2:29]3)=[O:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CCC(F)(F)CC1
Agent: Cl
Product: Cc1c(C(=O)NN2CCC(F)(F)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Form the acid chloride from 3.6 mmol of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid and react it with 2.6 mmol of the product of Example 28 using the general procedure set forth in Example 39, to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:22](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:22][NH:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CN(C)CCC=C1c2cc(N)ccc2CCn2cccc21
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc2c(c1)C(=CCCN(C)C)c1cccn1CC2
Reaction time: 2 h

Procedure:
A solution of 9-amino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine in triethyl orthoformate (2.8 g.; 10 mmoles in 80 ml.) was refluxed for 5 hours. The volatiles were removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol was stirred in an ice bath as sodium borohydride (0.88 g., 0.024 moles) was added over a period of 10 minutes. The mixture was stirred for a period of 2 hours. After concentration of the ethanol, the residue was dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:36][Mg]Br.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:8][CH:9]=1)([CH3:36])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCCc1nc(C)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1nc(C)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 35 %

Procedure:
4′-{[1-(4-Acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.2 g) was dissolved in tetrahydrofuran (12 mL), methylmagnesium bromide (1.0 M tetrahydrofuran solution, 6.4 mL) was added at −78° C., and the mixture was stirred for 1 hr. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.45 g, 35%) as a pale-yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:18](=O)[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:41](C(OC(C)(C)C)=O)[C:42]([O:44]C(C)(C)C)=[O:43].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:17]=[C:13]2[C:12]([C:18]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[C:41]([C:42]([OH:44])=[O:43])[O:16][C:14]2=[O:15])=[CH:11][C:10]=1[O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(C(=O)O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a solution of 5-benzyloxy-4-methoxy-2-(3,4,5-trimethoxybenzoyl)-benzoic acid (90 g) in dimethylformamide (900 MI) are added potassium carbonate (60.5 g) and di-tert-butyl bromomalonate (64.6 g), and the mixture is stirred at room temperature for three hours. To the reaction mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. To the residue is added a 4M solution of hydrogen chloride in ethyl acetate (500 ml), and the mixture is stirred at room temperature for five hours. The precipitated crystals are collected by filtration, washed, dried, and dissolved in a mixture of acetic acid (40 ml) and dioxane (80 ml). The mixture is heated under reflux for five hours, and the precipitated crystals are collected by filtration. washed, and dried to give 7-benzyloxy-6-methoxy-4-(3,4,5-trimethoxyphenyl)isocoumarin-3-carboxylic acid (70.0 g) as listed in Table 59.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22](O)(=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N=C=NCCCCCC)CCCCC>C(Cl)Cl>[C:22]([O:18][CH2:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=1)(=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCC(=O)O
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: CCCCCCN=C=NCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)OCCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of the compound 22 (345 mg, 1 mmol), undecanoic acid (186 mg, 1 mmol) and N,N-dimethylaminopyridine (122 mg, 1 mmol) in methylene chloride (3 mL) was added 1,3-dihexylcarbodiimide (206 mg, 1 mmol) under ice-cooling, and stirred at room temperature overnight. The precipitated insoluble matter was filtered, and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (hexane - ethyl acetate (1:1)) to give the compound 106 (461 mg, 90%) as oil. Rf 0.50 (1:1 EtOAc - hexane). 1H-NMR (CDCl3): δH0.88 (3 H, S, t-like, CH3), 1.23 (6 H, d, J 6.9 Hz, (CH3)2CH), 1.25 (14 H, bs, --CH2 --), 3.09 (1 H, sep, J 6.9 Hz, (CH3)2CH), 3.10 (2 H, t, J 7.2 Hz, CH2), 3.49 (3 H, s, NCH3), 4.42 (2 H, t, J 7.2 Hz), 6.80 (2 H, d, J 1.8 Hz, arom 2- and 6-H), 7.11 (1 H, t, J 1.8 Hz, arom 4-H) Elementary analysis (for C26H38N2O2SCl2) Calcd. : C, 60.81% H, 7.46% N, 5.45% S, 6.24% Cl, 13.81% Found: C, 60.55% H, 7.39% N, 5.54% S, 6.14% Cl, 13.81%
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>O.Br>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: BrBr
Agent: Br
Solvent: O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.6 %

Procedure:
A solution of 4-fluoro-2-nitroaniline (39.03 g, 250 mmol) in water (900 ml) and 48% hydrobromic acid (1500 ml) was treated with bromine (15.26 ml, 46 g, 288 mmol) added dropwise over 20 min. The resulting precipitate was stirred at ambient temperature for a further 45 min then diluted with ice-water (2000 ml). The solid product was collected by filtration, washed with cold water and dried to afford 2-bromo-4-fluoro-6-nitrophenylamine as an orange powder (55 g, 94%): δH (360 MHz, CDCl3) 6.49 (2H, br), 7.56 (1H, dd, J 7 and 3), 7.90 (1H, dd, J 9 and 3).
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:25]1[CH2:35]CN2C(=NCCC2)C[CH2:26]1.C(I)(C)C>C(#N)C>[CH:25]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[C@@H:13]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:14]([OH:16])[CH2:15][C@@H:2]1[OH:1])([CH3:35])[CH3:26]
Reactant: CCCC/C=C/CC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CC(C)I
Product: CCCC/C=C/CC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound 28 obtained obove (237 mg, 0.70 mmole) was dissolved in acetonitrile (3 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.178 ml, 1.2 mmole) and isopropyl iodide (0.12 ml, 1.2 mmole) were added thereto and the mixture was stirred at room temperature for 15 hours. Then, the reaction mixture was treated following the procedure similar to that of Example 5, to yield 266 mg of the title compound 29 as a colorless oil (quantitative).
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([C:7](=[O:6])[CH3:8])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(-c2ccccn2)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After 21 ml of a 3M methyl magnesium bromide-diethyl ether solution was added dropwise to a solution of 3.10 g of 4-(2-pyridyl)benzonitrile in 120 ml of dichloromethane under ice-cooling in a nitrogen atmosphere, the mixture was stirred at room temperature for 20 hours. After the reaction, an aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, followed by stirring of the resulting mixture. The ethyl acetate layer was separated from the reaction mixture, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain the crude desired compound as crystals. Further, the crude compound was washed with diisopropyl ether-hexane to obtain 1.56 g of the desired compound.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)C>C1COCC1.Cl.C(OCC)(=O)C.O>[OH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)c1ccc(CO)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CO)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Alcohol 1 (10.09 g, 48 mmol) was dissolved in a mixture of THF (100 ml) and 2 M HCl (100 ml) and stirred for 1 hour. The solvent was evaporated and the residue obtained was dissolved in ethyl acetate (100 ml) and water (100 ml). The phases were separated and the organic phase was washed with water (100 ml), dried over magnesium sulphate, and evaporated to yield 2 as a white solid (6.54 g, 48 mmol, 100%). Rf=0.54 (ethyl acetate/chloroform, 1:1); νmax=3327, 1689, 1607, 1206, 1010, 823 cm−1; 1H NMR (250 MHz, CDCl3) δ=10.02 (s, 1H, CHO), 7.89 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CHO), 7.54 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CH2OH), 4.82 (d, 3J(H,H)=5.9 Hz, 2H, CH2OH), 1.94 (t, 3J(H,H)=5.9 Hz, 1H, CH2OH); 13C NMR (75 MHz, CDCl3) δ=192.0 (CHO), 147.7 (ArCCOH), 135.7 (ArCCHO), 130.0 (ArCH α to ArCCHO), 127.0 (ArCH α to ArCCH2OH), 64.6 (CH2OH); HRMS (ESI−): m/z calculated for C8H7O2 [M−H]−: 135.0446, found 135.0448; elemental analysis calcd (%) for C8H8O2 (136.15): C, 70.57; H, 5.92. found: C, 70.70; H, 6.00.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.[BH3-]C#N.[Na+]>C(O)C>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH:39]6[CH2:40][CH2:41][O:36][CH2:37][CH2:38]6)[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: O=C1CCOCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C5CCOCC5)C4)cc2OCC3)n(C(C)C)n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14), 2,4,10,12-pentaene (60 mg, 0.13 mmol) and tetrahydropyran-4-one (26 mg, 0.26 mmol) in ethanol (10 mL) was added Ti(Oi-Pr)4 (74 mg, 0.26 mmol). After being stirred at 20° C. for 20 min, NaBH3CN (16 mg, 0.26 mmol) was added and stirred at 20° C. for 16 h. The solvent was removed and several drops of water were added. The solid was filtered off and the filtrate was evaporated to afford the crude product, which was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 226 (35 mg, 50% yield). LCMS (ESI): RT=4.97 min, m/z: 557.4 [M+H+]. 1H NMR (500 MHz, MeOH-d4) δ 8.48 (d, J=8 Hz, 1H), 7.25 (s, 1H), 7.41 (s, 1H), 7.09 (d, J=8 Hz, 1H), 7.00 (s, 1H), 5.94 (t, J=13 Hz, 1H), 4.54 (d, J=5 Hz, 4H), 3.95 (d, J=6.5 Hz, 5H), 3.35 (t, J=25 Hz, 3H), 3.25 (s, 1H), 3.00 (d, J=6.5 Hz, 2H), 2.51-2.54 (m, 2H), 2.38 (s, 3H), 2.12 (d, J=11 Hz, 1H), 1.86-1.62 (m, 6H), 1.56-1.49 (m, 6H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:20]([O:21][CH3:22])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.67 h
Yield: 81 %

Procedure:
To a suspension of 136.8 g (0.60 mol) 3-benzyloxybenzoic acid in 1200 ml dichloromethane 60.6 g (0.6 mol) triethylamine was added at 10° C. A solution of 64.8 g (0.60 mol) ethyl chloroformiate in 100 ml dichloromethane was added over a period of 15 minutes keeping the temperature between 10° C. and 15° C. After stirring for 40 minutes and addition of 58.2 g (0.60 mol) N,O-dimethylhydroxylamine hydrochloride a solution of 60.6 g (0.60 mol) triethylamine was added over a period of 20 minutes at 10–15° C. After additional strirring for 30 minutes water was added and the organic layer dried over sodium sulphate. Fractionated distillation in vacuo yielded 131.9 g (81%) B1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:18])=[N:6][CH:5]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C=O)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Yield: 103.4 %

Procedure:
6-[3-(4-Fluoro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (2.50 g, 7.02 mmol) and sodium borohydride (553 mg, 14.0 mmol) in methanol (125 mL) were stirred for 2 h at room temperature. Addition of 10% aqueous citric acid (200 mL) and extraction with ethyl acetate yielded 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (2.60 g, quant.) as white solid. MS: m/e=359.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1.Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(O)(C)C.C(=O)(O)[O-].[Na+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1
Reactant: Nc1ccc(Oc2nccnc2C2CCCOC2)cc1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4C4CCCOC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.082 g, 0.30 mmol) and 2-chlorobenzothiazole (0.039 mL, 0.30 mmol) were mixed in isopropyl alcohol (0.50 mL) in a microwave tube. The tube was sealed, and the reaction mixture was refluxed for 2.5 h. The reaction mixture was cooled to room temperature, diluted with sat. sodium bicarbonate, and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 405.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH2:4][C@H:3]1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=O.O1CCCC1.C(O)(=O)C>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:9][C@@H:3]3[CH2:4][S:5](=[O:7])(=[O:8])[CH2:6][C@H:2]3[NH2:1])[CH2:12]2)=[CH:23][CH:22]=1
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 16.5 h
Yield: 61.2 %

Procedure:
[(3R,4S)-4-Amino-1,1-dioxo-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-methanone (560 mg, 1.46 mmol) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 58 mL, 58 mmol) and stirred for 16.5 h . The mixture was treated slowly with 20% acetic acid in methanol (38 mL), and the resulting mixture was stirred at room temperature for 5.5 h . The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated to provide a gum. This was purified by flash column chromatography (4% methanol/dichloromethane, containing 0.4% ammonium hydroxide) to provide the product (304 mg, 61%) as a white solid. 1H NMR (300 mHz, CD3OD) δ7.13 (m, 2H), 6.96 (m, 2H), 3.36 (m, 3H), 2.87 (m, 3H), 2.78 (m, 1H), 2.56 (m, 1H), 2.49 (m, 2H), 2.40 (m, 2H), 1.95 (m, 1H), 1.8-1.6 (m, 4H), 1.50 (m, 1H), 0.95 (m, 1H), ESI MS: (M+H)+=341.2.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:25]\[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:20][CH:19]=1>O1CCCC1.[Cu]I.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>[CH3:40][C:30]1[CH:29]=[C:28]([O:27][CH2:26]/[CH:25]=[C:24](\[C:21]2[CH:20]=[CH:19][C:18]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:23][CH:22]=2)/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH:39]=[CH:38][C:31]=1[O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
4-Propargylmorpholine (193 mg, 1.55 mmol) and diisopropylamine (0.51 mL, 3.64 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (12 mg, 0.063 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) were added. The reaction mixture was stirred at ambient temperature for 19 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]-phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.