Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:8]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:9]=[CH2:10]
Reactant: CCOC(=O)CBr
Reactant: C=CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCc1cc(Br)ccc1OCC(=O)OCC
Temperature: 25 °C
Yield: 70.2 %

Procedure:
Ethyl bromoacetate (1.68 g) was added to a stirred suspension of 2-allyl-4-bromophenol (2.13 g) and potassium carbonate (1.50 g) in butan-2-one (15 ml). The mixture was heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. Water (100 ml) was added to the filtrate and the aqueous phase was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, washed with brine (2×25 ml), dried (MgSO4) and evaporated to give a solid which crystallised from hexane to give ethyl 2-allyl-4-bromophenoxyacetate (2.10 g), mp 70.5° C.; microanalysis, found: C, 52.0; H, 5.10%; C13H15BrO3 requires: C, 52.2; H, 5.05%; NMR (CDCl3) 1.29 (3H, t), 3.42 (2H, d), 4.25 (2H, q), 4.58 (2H, s), 5.07-5.17 (2H, m), 5.88-6.18 (1H, m), 6.60 (1H, d) and 7.20-7.27 (2H, m); m/z 300 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[O:21])=[C:18]([CH3:29])[NH:17][C:16]=1[CH:30]=O>>[CH3:14][C:15]1[C:19]([C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[O:21])=[C:18]([CH3:29])[NH:17][C:16]=1[CH:30]=[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3][CH2:2][OH:1])[NH:8][C:7]1=[O:13]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCO)c32)c(C)c1C(=O)N1CCN(C)CC1
Yield: 55 %

Procedure:
4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one (71 mg, 0.4 mmol) was condensed with 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give 90 mg (55%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C1COCC1>[CH3:1][NH:2][S:18]([CH:15]1[CH2:16][CH2:17][N:13]([C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])[CH2:14]1)(=[O:20])=[O:19]
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Methylamine (40 wt % in H2O, 1 mL) was added to a solution of 3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester (256 mg, 0.843 mmol) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, and then warmed to room temperature and stirred for 2 hrs. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on neutral alumina, eluting with CH2Cl2/MeOH (99:1 to 95:5), gave benzyl 3-[(methylamino)sulfonyl]-1-pyrrolidinecarboxylate (173 mg, 69%): 1H NMR (CDCl3) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.9 Hz, 2H), 4.27 (d, J=42.6 Hz, 1H), 3.80-3.70 (m, 4H), 3.50 (m, 1H), 2.82 (d, J=4.9 Hz, 3H), 2.35 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([C@H:7]2[O:12]C(=O)[C@@H](O)[C@H]2O)[CH2:4][O:3]1.I([O-])(=O)(=O)=O.[Na+].[OH-].[Na+].[BH4-].[Na+]>O.CC(C)=O>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][OH:12])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H]([C@H]2OC(=O)[C@@H](O)[C@H]2O)O1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a stirring suspension of 5,6-O-isopropylidene-L-gulono-1,4-lactone (15.16 g, 69.5 mmol) in water (0.3 L) was added solid sodium periodate in small portions at 3-5° C. The pH of the mixture was adjusted to 5.5 with 1N aqueous sodium hydroxide. The suspension was stirred for 2 hrs at ambient temperature, then saturated with sodium chloride (20.0 g) and filtered. To the filtrate, at 3-5° C., was added sodium borohydride (10.5 g, 0.278 mol) in small portions. The reaction mixture was stirred for 18 h at ambient temperature. Acetone (100 mL) was added to destroy the excess of sodium borohydride, and the stirring was continued for 30 minutes. The acetone was removed under reduced pressure and the aqueous residue was extracted with dichloromethane (3×300 mL) and EtOAc (3×300 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to give (R)-(+)-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (5.07 g, 55.7%) as a colorless clear liquid: MS(APCI+)=132.9 (M++1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.CO[CH:33](OC)[N:34]([CH3:36])[CH3:35]>>[CH3:33][N:34]([CH:36]=[C:7]1[C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1=[O:1])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC(=O)C1
Reactant: COC(OC)N(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CN(C)C=C1C(=O)CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
56.0 g (of 1,1-dimethylethyl 3,5-dioxo-1-piperidinecarboxylate having the empirical formula C10H15NO4 (prepared by a method similar to that described in Heterocycles, 22, 2769-2773, (1984), replacing methyl chloroformate with (BOC)2O, are prepared as a suspension. 55.5 ml of N,N-dimethylformamide dimethyl acetal at 95% are added at room temperature. The medium is stirred for half an hour at 80° C. and then for 3 hours at 50° C. The solvent is evaporated off under reduced pressure. 79 g of 1,1-dimethylethyl 4-[(dimethylamino)methylene]-3,5-dioxo-1-piperidinecarboxylate having the empirical formula C13H20N2O4 are thus obtained. The corresponding yield is 99%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([SH:8])[CH2:4][CH2:3]1.[H-].[Na+].CN(C)C=[N:14][S:15]([C:18]1[S:19][C:20](Br)=[CH:21][CH:22]=1)(=[O:17])=[O:16]>CN(C=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([S:8][C:20]2[S:19][C:18]([S:15]([NH2:14])(=[O:17])=[O:16])=[CH:22][CH:21]=2)[CH2:4][CH2:3]1
Reactant: O[C@H]1CC[C@H](S)CC1
Reactant: CN(C)C=NS(=O)(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(S[C@H]2CC[C@H](O)CC2)s1
Reaction time: 8 h

Procedure:
Trans-4-Hydroxycyclohexylmercaptan (9.92 g, 0.075 mol) in DMF (10 ml) was added dropwise to a stirred mixture of NaH (3.45 g, 50 % oil, 0.075 mol) and DMF (40 ml). When gas evolution was complete, N,N-dimethyl-N'-(5-bromothiophene-2-sulfonyl)formamidine (14.85 g, 0.05 mol) was added in one portion, rinsed in with DMF (10 ml) and the resulting mixture was heated on the steam bath for 1 hour. The DMF was removed under reduced pressure and the residue was stirred with methanol (50 ml) and 10% sodium hydroxide solution (50 ml) overnight. The methanol was evaporated and the resulting aqueous solution was added to 10% HCl (400 ml) and chilled. The solid that separated was collected and washed with water. The residue was triturated with 1-chlorobutane to give a solid, (12.0 g) after drying. Recrystallization from water followed by dichloroethane gave material with m.p. 145°-147° C.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CN
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC)s1
Yield: 56 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using methylamine (2M solution in THF) instead of rac-2-amino-1-butanol, to the title compound (89 mg, 56%) which was obtained as a white solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=320.1 [M+H]+.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:22]=4[C:23]([CH3:38])=[N:24][N:25]5[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=4)=[O:19])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1>FC(F)(F)C(O)=O.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH3:38])=[N:24][N:25]4[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:19])=[CH:16][N:17]=[C:11]2[CH:10]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCC6COC(C)(C)O6)ccn45)cccc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCC(O)CO)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11 mg, 0.02 mmol) was taken up in 50% trifluoroacetic acid/water and stirred at ambient temperature for 1 hour. Concentrated and dried under high vacuum for an hour before treating with excess 2 M hydrochloric acid in diethyl ether. The solution was stirred for an hour and then concentrated to give 7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a colorless residue (8 mg). MS m/z 487.2 (M+1, APCI+).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([NH:15][C:16]([NH2:18])=[S:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>C(OCC)(=O)C>[N:15]1[C:5]2[C:14]3[C:9]([CH:8]=[CH:7][C:6]=2[S:17][C:16]=1[NH2:18])=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: NC(=S)Nc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Nc1nc2c(ccc3ccccc32)s1
Temperature: 25 °C
Yield: 74 %

Procedure:
To 160 ml thionyl chloride 64.0 g (0.32 mol) of 1-(1-naphthyl)-2-thiourea was added portionwise while the temperature of the reaction mixture was kept at 30°-40° (internal temperature). After the addition was completed, an additional 80 ml of thionyl chloride was added and the mixture was heated at 50°-55° for 4 hours. It was cooled to room temperature and diluted with 400 ml of ethyl acetate and filtered. The filtrate in 400 ml of water was basified with concentrated ammonium hydroxide and the aqueous suspension was extracted with ethyl acetate (3×200 ml). The combined ethyl acetate solutions were dried (MgSO4) and the solvent was removed under reduced pressure to give 46.6 g (74%) of naphtho[1,2-d]thiazol-2-amine, mp 186°-188°.
Reaction SMILES: [C:1]1([C:11]([C:13]2[CH:41]=[CH:40][C:16]3[N:17]([CH2:21][CH2:22][O:23][C:24]4[CH:39]=[CH:38][C:27]([CH:28]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=4)[C:18](=[O:20])[S:19][C:15]=3[CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OC(C)C)(C)C>>[C:1]1([C:11]([C:13]2[CH:41]=[CH:40][C:16]3[N:17]([CH2:21][CH2:22][O:23][C:24]4[CH:39]=[CH:38][C:27]([CH2:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=4)[C:18](=[O:20])[S:19][C:15]=3[CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc5ccccc45)ccc32)cc1)C(=O)OC
Solvent: CC(C)OC(C)C
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc5ccccc45)ccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Example 40, starting from the compound obtained in Example 47. The recrystallisation solvent is isopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:11][C@H:12]1[NH:17][C@@H:16]([CH3:18])[CH2:15][N:14](C2C=C3C(CCN3)=CC=2F)[CH2:13]1>>[CH3:18][C@H:16]1[NH:17][C@@H:12]([CH3:11])[CH2:13][N:14]([C:10]2[CH:9]=[C:8]3[C:4]([CH2:5][CH2:6][NH:7]3)=[CH:3][C:2]=2[CH3:1])[CH2:15]1
Reactant: Cc1ccc2c(c1)CCN2
Reactant: C[C@@H]1CN(c2cc3c(cc2F)CCN3)C[C@H](C)N1
Product: Cc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)NCC2

Procedure:
The title compound was prepared from 5-methylindoline using similar procedures to those described in D4, D5 and D6 above. MH+ 246.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:34]=[N:33][C:12]2[O:13][C:14]([CH3:32])([CH3:31])[C:15](=[O:30])[N:16]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[C:53](=O)([O-])[O-:54].[Cs+].[Cs+]>[Cu](I)I.O.CO>[CH3:53][O:54][C:9]1[CH:34]=[N:33][C:12]2[O:13][C:14]([CH3:32])([CH3:31])[C:15](=[O:30])[N:16]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Br)cc32)CC1
Agent: I[Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Temperature: 80 °C
Reaction time: 21 h
Yield: 24.9 %

Procedure:
To a toluene suspension (5.6 ml) of tert-butyl 4-(7-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (Example 52-1) (1.11 g), copper iodide (24.0 mg), 3,4,7,8-tetramethyl-1,10-phenanthroline (59.6 mg) and cesium carbonate (1.23 g) was added methanol (0.204 ml), followed by stirring at 80° C. for 21 hours. After the reaction solution was brought back to room temperature, water was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-methoxy-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (246 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15]>>[OH:15][CH2:14][C@@H:13]1[CH2:16][CH2:17][CH2:18][N:12]1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Clc1ccc2ccccc2n1
Product: OC[C@@H]1CCCN1c1ccc2ccccc2n1
Yield: 107.5 %

Procedure:
The title compound (6 g, 100%) was prepared as a syrupy liquid from 2-chloroquinoline (4 g) and L-prolinol (14.8 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH2:7].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28]([NH:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1ncco1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ncco1
Yield: 62 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use oxazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 62% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 7.45-7.30 (m, 5H), 7.13 (s, 1H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.49 (d, J=5.7 Hz, 2H), 2.54 (m, 3H); MS (ES+) m/z 423.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:35])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:34].[Li+].[OH-].Cl>C1COCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:35])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:34]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(C(=O)NC(C(=O)O)C(C)C)on2)ccc1NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the crude compound of step 8, LiOH (3.0 equiv.) and 50 ml of 5:1 THF/water was stirred at room temperature for 15 minutes. The reaction mixture was slightly acidified to pH <7 by adding 2N HCl and then evaporated to dryness under vacuum. The residue was dissolved in a chloroform and methanol mixture, adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, and then eluted with 2-15% methanol in chloroform to provide the title compound as a pale green solid after drying in vacuo; 1H NMR (300 MHz, DMSO-d6) δ: 0.85-0.88 (d, J=6.6 Hz, 6H), 2.14-2.19 (m, 1H), 2.34 (s, 3H), 3.92-3.96 (m, 1H), 7.11-7.16 (m, 2H), 7.24-7.31 (m, 1H), 7.60 (S, 1H), 7.67-7.70 (d, J=8.7 Hz, 1H), 7.76 (s, 1H), 8.01-8.04 (m, 2H), 8.86 (s, 1H), 9.24 (s, 1H); ms (ESI) m/z 473.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][CH:11]=[N:10][C:9]=2[CH:13]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.[OH-].[Na+]>C1COCC1.O>[S:12]1[C:8]2[CH:7]=[CH:6][C:5]([CH2:3][OH:2])=[CH:13][C:9]=2[N:10]=[CH:11]1
Reactant: COC(=O)c1ccc2scnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc2scnc2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a −78° C. cooled solution of benzothiazole-5-carboxylic acid methyl ester (1 eq.) in dry THF under nitrogen was slowly added a solution of LiAlH4 (1M in THF, 1.5 eq.). The reaction was stirred at −78° C. for 2 h, then warmed to 20° C. EtOAc was added to the reaction, then aqueous NaOH (2N) and finally water. The reaction mixture was stirred at 20° C. for 30 min, then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1) to afford benzothiazol-5-yl-methanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9]1>>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)=CCCBr
Product: CC(C)=CCCn1cc(C=O)c2ccccc21
Yield: 97.7 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.52 g of 5-bromo-2-methyl-2-pentene and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.06 g of 1-(4-methyl-3-pentenyl)indole-3-carbaldehyde as colorless crystals. The yield thereof was found to be 98%.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1)=[O:5]>CCO.O=[Pt]=O>[CH3:1][O:2][N:3]([CH3:26])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]1)=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CON(C)C(=O)c1cccc(F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-(2-(N-methoxy-N-methylcarbamoyl)-6-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.235 mmol) and PtO2 (180 mg) in EtOH (19 mL) was shaken in a Parr flask for 1 h15 under 51 psi of H2. The reaction was monitored by LC/MS. Unreacted SM was detected, so another 150 mg of PtO2 (total: 450 mg, 30 wt %) was then added and the mixture was hydrogenated under 50 psi for another 3 h. Mostly desired product was detected after 4 h by LC/MS (Rt=2.83 min). The catalyst was filtered off and the solution was concentrated in vacuo to yield 435 mg of tert-butyl 4-(2-(N-methoxy-N-methylcarbamoyl)-6-fluorophenyl)piperidine-1-carboxylate as a clear thick oil which was used as is for the next step. LC/MS ES+1: 367.38.
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18]C)[C:15]([Cl:20])=[CH:14][C:13]=2[F:21])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br>O>[Cl:20][C:15]1[CH:14]=[C:13]([F:21])[C:12]([C:3]2[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:17][C:16]=1[OH:18]
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl
Agent: Br
Solvent: O
Product: Oc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl

Procedure:
8.5 g (0.0263 mol) of 3-fluoro-2-(4-chloro-2-fluoro-5-methoxyphenyl)-5-trifluoromethylpyridine were added with stirring to 110 ml of 47% strength hydrobromic acid, and the mixture was refluxed for 2 h. After cooling, the clear solution was poured into 500 ml of water and extracted with methylene chloride. The organic phase was extracted with 1 N sodium hydroxide solution and the extract was acidified and extracted with ethyl acetate. Drying and concentration yielded 6.7 g (82.1% of theory) of the title compound of mp. 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 160 °C
Yield: 87.9 %

Procedure:
A mixture of 2-chloro-4-methoxy-phenol (7.93 g, 0.05 mol), 2-bromothiazole (9.0 g, 0.055 mol) and potassium carbonate (7.6 g, 0.055 mol) in dimethyl sulfoxide was heated at 160° C. under nitrogen for 4 hours. The solution was cooled and treated with water, and the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give 30 g of the crude material, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 10.62 g of the product as a light yellow oil (88% yield), 1H NMR (300 MHz, CDCl3) δ ppm 3.81 (s, 3H) 6.80 (d, J=4.04 Hz, 1H) 6.85 (dd, J=9.19, 2.94 Hz, 1H) 7.01 (d, J=2.94 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H) 7.27 (d, J=8.82 Hz, 1H). MS (ESI), m/z 241.9 (M+H)+.