Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:33])[CH3:32])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(C(C)=O)cc1)C(=O)CC
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(C)=O)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 2-(4-acetylbenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1>>[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Nc1cc(Br)ccn1
Product: Nc1cc(N2CCc3ccccc3C2)ccn1

Procedure:
Following the general method described in example 24, 4-bromo-pyridin-2-yl-amine (H. J. den Hertog, Recl.Trav.Chim.Pays-Bas, 1945, 64, 85) was reacted with 1,2,3,4-tetrahydro-isoquinoline. The crude product was chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH=200/10/1) and crystallized to yield the title compound as an off-white crystalline material. Mp. 160-161° C. (CH3CN), MS: m/e=226 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:35]=[CH:34][C:20]([CH2:21][O:22][C:23](=[O:33])[CH2:24][NH:25]C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)[N:3]=1.ClCCl.Cl.C(OCC)(=O)C>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:35]=[CH:34][C:20]([CH2:21][O:22][C:23](=[O:33])[CH2:24][NH2:25])=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CN)cc2)n1
Yield: 47.6 %

Procedure:
A mixture of 2-tert-butoxycarbonylamino-acetic acid 4-[4-amino-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazin-2-yl-amino]-benzyl ester (1.0 g, 2 mmol), dichloromethane (20 ml), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 ml) was stirred for 12 hours. The reaction mixture was poured into ethyl acetate (100 ml). The solid filtered and dried under reduced pressure to provide the hydrochloride salt of the title compound (0.38 g, 84% yield). 1H NMR (CD3OD) δ 7.75-8 (br s, 2H), 7.74 (s, 1H), 7.56-7.43 (m, 6H), 5.36 (s, 2H) 3.67 (s, 2H) 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](O)[CH2:22][CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:19][CH2:18][C:17]4([O:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Clc1cccc(C#CC2=NOC3(CCC4(CC3)OCCCO4)C2)c1
Yield: 75.3 %

Procedure:
A solution of the compound of Example 32 (0.41 g, 1.42 mmol), 1,3-propandiol (0.15 g, 1.95 mmol) and p-toluensulfonic acid. H2O (7.5 mg, 0.04 mmol) in 30 mL of benzene was stirred at reflux for 10.5 h, removing water with a Dean-Stark Apparatus. Dilution with water, washing with aq. 5% NaHCO3, drying the organic layer over Na2SO4 afforded the title compound as dense yellow oil. This was further purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 7:3) giving a white solid. Yield: 75.3%.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40].C(O)C>C(O)C>[ClH:40].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Solvent: CCO
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 0.21 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 4 mL of ethanol, 4 mL of a 6.0 mol/L hydrogen chloride/ethanol solution was added at room temperature, and the mixture was stirred for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.21 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]([O:71][CH3:72])=[O:70])=[CH:66][CH:65]=1>>[CH3:72][O:71][C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)s1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)s1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with methyl 5-aminothiophene-2-carboxylate (PrincetonBio) (0.084 g, 0.53 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-thiophene-2-carboxylic acid methyl ester as a off white solid (Yield 0.05 g, 19%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.[F:25][C:26]1[CH:27]=[C:28]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[O:34][C:33]=2CO)[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl.CO>[Br:24][CH2:21][C:33]1[O:34][C:35](=[O:42])[C:36]2[C:41]([C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2
Reactant: O=c1oc(CO)c(-c2cccc(F)c2)c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=c1oc(CBr)c(-c2cccc(F)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Triphenylphosphine (265 mg, 1.01 mmol) and perbromomethane (335 mg, 1.010 mmol) were added to a solution of 4-(3-fluorophenyl)-3-(hydroxymethyl)-1H-isochromen-1-one (intermediate B3, 210 mg, 0.777 mmol) in DCM (6.5 ml) and the mixture was stirred overnight at RT. Further triphenylphosphine (265 mg, 1.010 mmol) and perbromomethane (335 mg, 1.01 mmol) were then added and left on stirring at RT for 6 hrs. The reaction was then diluted with MeOH (1 ml) and straightforward purified on 50 g Biotage silica cartridge eluting with a gradient of Hexane and EtOAc to give the title compound (154 mg, 59.5%) as a yellow solid.
Reaction SMILES: S(OC)(OC)(=O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O.C([O-])([O-])=O.[K+].[K+].[ClH:20].[CH:21]1([CH:24]([NH2:28])[CH:25]2[CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[ClH:20].[CH:21]1([CH:24]([CH:25]2[CH2:27][CH2:26]2)[NH:28][C:9]2[CH2:10][CH2:11][CH2:12][N:8]=2)[CH2:23][CH2:22]1
Reactant: NC(C1CC1)C1CC1
Reactant: O=C1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: C1CN=C(NC(C2CC2)C2CC2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 0.2 mol (25.2 g) of dimethyl sulphate and 0.2 mol (17 g) of 2-pyrrolidinone is heated at 60° C. overnight. The reaction mixture is poured into a saturated iced K2CO3 solution. The aqueous phase is extracted twice with ether, and the combined organic phases are dried and concentrated. The residue is then distilled under reduced pressure. 2 mrnmol of the resulting product are dissolved in 20 ml of methanol, and 2 mmol (295 mg) of dicyclopropylmethylamine hydrochloride are added. The reaction mixture is stirred at 50° C. for 2 hours. After evaporation of the methanol, the residue is taken up in water, rendered alkaline and extracted twice with ether. The organic phase is dried, concentrated and purified to yield the expected product. The corresponding, hydrochloride is obtained by the action of a titrated solution of hydrochloric acid in ethanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:29](=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)=[O:40])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(C2CN(Cc3ccccc3)CCO2)cc1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (1.89 g, 5.7 mmol) in THF (30 mL), at −78° C., was added dropwise n-butyl lithium (2.85 mL; 2.5 mol/l in hexanes; 7.1 mmol). The mixture was stirred for 20 min. at −78° C., and subsequently N-Methoxy-N-methyl-3-trifluoromethyl-benzamide (2.66 g, 11.4 mmol) was added. The mixture was allowed to warm to RT and stirred overnight. The resulting mixture was partitioned between an aqueous saturated NH4Cl solution and EtOAc. The layers were separated. The organic layer was washed with a saturated aqueous NaHCO3-solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:heptanes 1:3) to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-methanone (0.84 g), which was used as such in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.C(OCC)(=[O:23])C>>[O:23]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1ccc(C(C)C)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(=O)c1ccc(C(C)C)cc1

Procedure:
Prepared from methyl 4-isopropylphenylacetate by the method described in Example 33a), except that the eluent used was 4:1 hexane:ethyl acetate and the product contained starting material. δH (250 MHz, CDCl3), 1.28 (6H, d, J 6.87), 2.99 (1H, heptet), 3.98 (3H, s), 7.37 (2H, d, J 8.25), 7.95 (2H, d, J 8.33).
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16]O)[OH:15])[OH:13])[OH:11])[OH:9])[CH2:3][CH2:4][CH3:5].[OH-:18].[Na+]>O>[CH2:2]([NH:6][CH:7]([C@:8]1([O:15][C@@H:14]([CH3:16])[C@@H:12]([OH:13])[C@@H:10]1[OH:11])[OH:9])[OH:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCNC(O)[C@@]1(O)O[C@@H](C)[C@@H](O)[C@@H]1O
Temperature: 15 °C
Reaction time: 27 h
Yield: 80 %

Procedure:
A reaction solution is is prepared by adding 170 ml of a bulk solution of N-n-butylglucamine hydrochloride with a concentration of 450 gm/L (by HPLC) to 210 ml of water in a 1-L bioreactor. The solution is adjusted to pH 5 by adding dilute sodium hydroxide and cooled to about 15° C. A total of 20 gm (wet weight) of washed G. oxydans cell paste is added and the reaction mixture is agitated (1000 rpm) and aerated (1 vvm) while controlling the temperature at 15° C. and pH at 5. After 27 hours, the HPLC assay indicates that over 97% of the substrate has been converted for a 80% yield of N-n-butylamino-6-deoxy-α-L-sorbofuranose.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].CO.[C:18]1(C)C=CC=CC=1.C(OC)(OC)OC>CCCCCCC.CCOC(C)=O>[CH3:18][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Cc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCBr
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCCCCCCCCCBr
Temperature: 70 °C
Reaction time: 16 h

Procedure:
12-Bromododecanoic acid (10 g, 35.8 mmol) was stirred with methanol (60 ml) and Toluene (180 ml). Trimethyl orthoformate (38 g, 358 mmol) and Amberlyst A-15 (ca. 1 g) were added. The reaction was mixed for 16 h. At some point the heating unit failed, So the reaction cooled from 70° C. to rt. The solution was heated to 70° C. and mixed for 24 h. TLC (2:1 heptane/AcOEt) indicated the reaction was incomplete. Trimethyl orthoformate (38 g, 358 mmol) and Amberlyst A-15 (1.4 g) were added, and the solution was stirred at 70° C. for 16 h. The sample was concentrated under vacuum to yield a brown oil (9.87 g). Vacuum distillation at 0.09 torr yielded two fractions of colorless oil (109-117° C., 6.95 g; 117-129° C., 1.17 g). These were combined and dissolved in AcOEt (100 ml) and washed with Sat. NaHCO3 (2×40 ml), dried over MgSO4 and concentrated under vacuum. The oil was dissolved in 20:1 AcOEt/TEA (10 ml) and added to a bed of silica (3 cm×7.5 cm dia). The column was eluted with AcOEt/TEA 20:1 (200 ml), and the filtrate was concentrated under vacuum. The oil was dissolved in AcOEt (100 ml) and washed with 1 N HCl (2×40 ml), dried over MgSO4 and concentrated under vacuum to yield a colorless oil (7.52 g, 72% yield).
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:13](OCCC(C)C)=O.[CH3:21][S:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[C:28]([CH3:36])[C:27]=1[O:37][CH3:38])(=[O:24])=[O:23]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[CH3:21][S:22]([O:25][C:26]1[C:27]([O:37][CH3:38])=[C:28]2[C:29](=[CH:30][CH:31]=1)[N:32]([C:33](=[O:35])[CH3:34])[N:13]=[CH:36]2)(=[O:24])=[O:23]
Reactant: CC(C)CCON=O
Reactant: COc1c(OS(C)(=O)=O)ccc(NC(C)=O)c1C
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(OS(C)(=O)=O)ccc2c1cnn2C(C)=O
Reaction time: 8 h
Yield: 141.2 %

Procedure:
Acetic anhydride (155?1, 1.65 mmol), tetrabutylammonium bromide (8.8 mg, 0.0274 mmol), potassium acetate (108 mg, 1.10 mmol) and isoamyl nitrite (0.096 ml, 0.274 mmol) were added to a solution of 4-(acetylamino)-2-methoxy-3-methylphenyl methanesulfonate (150 mg, 0.549 mmol) in ethyl acetate (1.5 ml) at room temperature. After 8 hours, isoamyl nitrite (0.037 ml, 0.713 mmol) was further added thereto. After another 2 hours, the mixture thus obtained was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-acetyl-4-methoxy-1H-indazol-5-yl methanesulfonate (110 mg, 70%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]([N:9]2[CH2:14][C@@H:13]([CH3:15])[O:12][C@@H:11]([CH3:16])[CH2:10]2)=[O:8])[S:5][CH:6]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][CH2:21][NH:22]2.C1(C)C=CC=CC=1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.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]>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][CH2:21][N:22]2[C:2]1[N:3]=[C:4]([C:7]([N:9]2[CH2:14][C@@H:13]([CH3:15])[O:12][C@@H:11]([CH3:16])[CH2:10]2)=[O:8])[S:5][CH:6]=1
Reactant: C[C@@H]1CN(C(=O)c2nc(Br)cs2)C[C@H](C)O1
Reactant: Clc1cccc2c1CCN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)c2nc(N3CCc4c(Cl)cccc43)cs2)C[C@H](C)O1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
(cis) (4-bromothiazol-2-yl) (2,6-dimethylmorpholino)methanone (step-1 of compound 45, 1.0 g, 3.28 mmol) and 4-chloroindoline (0.55 g, 3.60 mmol) were added to seal tube containing toluene (25 ml). Sodium tert-butoxide (0.47 g. 4.91 mmol) was added, the nitrogen gas was bubbled through reaction mixture for 15 minutes and tris(dibenzylideneacetone)dipalladium(0) (0.15 g, 0.16 mmol) was added under nitrogen and the tube was sealed. The reaction mixture was heated at 100° C. for 18 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and diluted with ethyl acetate (100 ml) and washed with water (25 ml). The organic layer was dried over sodium sulfate filtered and concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (0.75 g, 60.6%). MS: m/z 378 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Br-].[CH2:11]([Zn+])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: [Br-]
Product: Cc1c(Cl)ncnc1Cc1ccccc1

Procedure:
Prepared from 4,6-dichloro-5-methylpyrimidine and benzyl zinc bromide (0.5 M solution in tetrahydrofuran) according to the procedure described in WO 2007/146824 as a colorless oil. 1H NMR (400 MHz, CDCl3): 8.78 (s, 1H), 7.33-7.18 (m, 5H), 4.19 (s, 2H), 2.36 (s, 3H); MS (EI) for C12H11ClN2: 219 (MH+).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:19]=[C:20]([OH:27])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23]>C(O)(=O)C>[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:19][C:20]=1[OH:27])([OH:24])=[O:23]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1O

Procedure:
A solution of 32.4 g. (0.15 mole) of 2-phenacylcyclohexanone, 23.0 g. (0.15 mole) of 4-aminosalicylic acid and 90 ml. of glacial acetic acid was heated under reflux for 7 hours, cooled, diluted with 90 ml. of water and extracted with ether. The ether solution was dried over sodium sulfate and concentrated. The residue was recrystallized from benzene-ethanol to provide 3.36 g. (7%) of yellow crystals, m.p. 193°-195°.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CS(O[CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)(=O)=O.O>CN(C=O)C>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:21]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 80 °C
Yield: 64 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.62 g, 14.3 mmol) in dry DMF (20 mL) under nitrogen was cooled by an ice-bath. A solution of 4-(pyrrolidin-1-ylmethyl)phenol—see e.g. Bioorganic & Medicinal Chemistry Letters, 15, 3834-3837 (2005)—(2.1 g, 11.9 mmol) in DMF (20 mL) was added drop-wise. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.9 g, 15.5 mmol) in DMF (10.0 mL) was added. The mixture was heated to 80° C. overnight and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic solutions were washed with brine, dried (MgSO4) and evaporated. The residue was purified twice by column chromatography on SiO2 using 10-100% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.5 g (64%) of 1A. 1H NMR (600 MHz, CDCl3): δ 1.43 (s, 9H), 1.77 (s, 4H), 2.47 (s, 4H), 3.54 (s, 2H), 3.95-4.02 (m, 2H), 4.24-4.30 (m, 2H), 4.82-4.88 (m, 1H), 6.67 (d, 2H), 7.23 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11]>N1C=CC=CC=1>[CH3:8][N:9]([CH3:13])[C:10]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:11]
Reactant: Cc1cc(N)no1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)N(C)C)no1
Yield: 56 %

Procedure:
To 3-amino-5-methylisoxazole (490.6 mg), pyridine (3 g) and dimethylcarbamoyl chloride (1.18 g) are added, and the resultant mixture is stirred at 60° C. for 5.5 hours. The pyridine is evaporated under reduced pressure. The residue is mixed with water (15 ml), adjusted to pH 1 with 5% hydrochloric acid and shaken with chloroform. The chloroform layer is evaporated to remove the chloroform. The residue is mixed with 1.5% methanolic sodium hydroxide solution (25 ml) and evaporated. The residue is extracted with chloroform again. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the chloroform. The residue is chromatographed on a thin layer of silica gel to give 1,1-dimethyl-3-(5-methyl-3-isoxazolyl)urea (0.4735 g) as crystals melting at 150.5° to 151.5° C. The yield is 56%.