Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[CH:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:25]>O1CCCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:25])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 40 °C
Yield: 101.7 %

Procedure:
A solution of 4-morpholinoaniline (8.3 g, 51.5 mmol) in 100 mL of tetrahydrofuran was treated with 3-hydroxymethylene-1,3-dihydro-indol-2-one (5.5 g, 30.9 mmol) in one portion. The reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated. The residue was treated with 125 mL of ethyl acetate and the resulting suspension was heated at 40° C. for 2 h. The suspension was cooled to room temperature and the solid collected by suction filtration and washed with ethyl acetate. The solid obtained was dried under vacuum to give the title compound (10.1 g, 92%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[CH3:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[CH:10]=[CH:11][C:12]=4[C:13]=3[N:14]=2)[CH:28]=[N:29][CH:30]=1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: Cc1cncc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cncc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3n2)c1
Temperature: 110 °C

Procedure:
2-Bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide 325D (100 mg, 0.267 mmol), 5-methylpyridin-3-ylboronic acid (51.1 mg, 0.373 mmol), PdCl2(dppf)-CH2Cl2 adduct (10.88 mg, 0.013 mmol), and Na2CO3 (2M) (0.666 mL, 1.333 mmol) were mixed with DME (4 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 110° C. in microwave for 1 hr. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 387.97 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.33 (s, 1H), 9.25 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.09 (d, 1H, J=8.6), 7.87 (s, 1H), 7.23 (s, 1H), 7.03 (dd, 1H, J=8.9, 2.1), 3.81 (m, 4H), 3.25 (m, 4H), 2.44(s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:19]=[C:18](F)[C:15]([C:16]#[N:17])=[C:14]([F:21])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:19]=[C:18]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:15]([C:16]#[N:17])=[C:14]([F:21])[CH:13]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a 500-mL RBF was added NaH (0.660 g, 27.5 mmol) and THF (100 mL). To this solution was added benzyl alcohol (2.385 mL, 22.94 mmol) in THF slowly via syringe, with external cooling (ice bath) when necessary. After the addition, the reaction mixture was stirred for 1 hour at room temperature. At this time, the mixture was transferred via syringe slowly to a solution of 4-bromo-2,6-difluorobenzonitrile (5 g, 22.94 mmol) in THF at 0° C. The solution was allowed to warm to room temperature and stirred over the weekend. The reaction was poured into water (50 mL), and extracted with EtOAc (3×100 mL). The organic layers were combined and dried over Na2SO4. The dried solution was filtered, and the filtrate was concentrated in vacuo to yield a pale yellow solid which was purified by flash chromatography (gradient elution 0-30% EtOAc in hexanes) to afford the title compound (3.911 g) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6): δ 5.35 (s, 2H), 7.27-7.66 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:9]([NH2:18])=[N:8][C:6]=2[N:7]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[C:9]([NH:18][C:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3ccncc3)c(N)nc2n1
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1ccncc1

Procedure:
Following the procedure of Example 2, 0.30 g of 2,7-diamino-6-(4-pyridyl)-pyrido[2,3-d]pyrimidine from Example 109 was reacted with 0.154 mL of tert-butyl isocyanate. The product was purified by medium pressure chromatography using silica gel and eluting with 90:10:1 EtOAc:MeOH:TEA, to afford the title compound, mp >350° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 338 (MH+ +1, 6), 339 (MH+ +2, 1), 84 (100).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>O>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([NH:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: NC1CCCCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), cyclohexylamine (40 mg, 0.41 mmol) and DIPEA (104.5 mg, 0.81 mmol) in dimethyl formide (2 mL) was stirred at room temperature for 2 h. Then water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was concentrated and the residue was purified by preparative HPLC to give 51 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one as a white solid. MS: 389 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13]COC)[CH:5]=[C:4]([O:17]COC)[C:3]=1[C:21](=[O:38])[CH2:22][CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32]COC)=[C:26]([O:36][CH3:37])[CH:25]=1.Cl.CO>CO>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[CH:5]=[C:4]([OH:17])[C:3]=1[C:21](=[O:38])[CH2:22][CH2:23][C:24]1[CH:25]=[C:26]([O:36][CH3:37])[C:27]([OH:32])=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COCOc1cc(OCOC)c(C(=O)CCc2cc(OC)c(OCOC)c(OC)c2)c(O)c1CCC(C)C
Agent: Cl
Solvent: CO
Product: COc1cc(CCC(=O)c2c(O)cc(O)c(CCC(C)C)c2O)cc(OC)c1O
Yield: 35.8 %

Procedure:
Next, 10.0 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone was dissolved in 25.0 ml of methanol, and 70 ml of a hydrochloric acid-methanol reagent was added to the solution and the mixture was refluxed in an argon atmosphere for 1 hour. The reaction liquid was concentrated under a reduced pressure and subjected to the column chromatography [230-400 mesh Kieselgel 60; eluting solvent=chloroform/methanol (20/1)] to obtain 2.7 g (yield=36.8%) of yellowish brown 1-(2,4,6-trihydroxy-3-isopentylphenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>O>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC
Solvent: O
Product: C=CCCCCCCCC

Procedure:
To a 250 ml high pressure kettle for polymerization, 80 ml of n-hexane, 8 g of catalyst obtained as above, 30 ml of 1-decene and 0.174 ml of water as a co-catalyst are added. 1-decene oligomerization is carried out under a condition of a temperature of 80° C. and a pressure of 1.0 MPa for 5 hours, after which the reaction is stopped and the catalyst is filtered out, the solvent n-hexane is removed by distillation under ambient pressure, and then unreacted monomer 1-decene and part of the dimers are removed by distillation under reduced pressure to produce the final oligomer. The conversion of 1-decene is 54.1 wt %. The oligomer has a kinematic viscosity at 40° C. of 16.51 mm2/s, a kinematic viscosity at 100° C. of 5.81 mm2/s and a viscosity index of 208.80.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[Br:10]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:10][C:8]1[CH:9]=[C:4]2[CH2:3][CH2:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36.4 %

Procedure:
The resulting 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614 mg, 5.11 mmol) and N-bromosuccinimide (1.09 g, 6.13 mmol) were dissolved in N,N-dimethylformamide (12 mL), and the solution was stirred for 2.5 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1), and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (370 mg, 1.86 mmol, 36%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4](F)([F:6])[F:5].C([Li])CCC.[CH:16](=[O:21])[CH2:17][CH:18](C)[CH3:19].Cl>O1CCCC1.CCCCCC>[F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[C:4]([F:6])([F:5])[CH:16]([OH:21])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)CC=O
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(O)C(F)(F)C(=O)C(F)(F)F
Temperature: 5 °C
Reaction time: 5 h

Procedure:
With stirring in a nitrogen atmosphere, a mixture of 111 g of 1,1,1,3,3,3-hexafluoro-2-propanol and 700 ml of tetrahydrofuran was cooled below −40° C., to which 500 ml of a n-hexane solution of 2.64M n-butyllithium was added dropwise. At the temperature, the reaction mixture was stirred for 30 minutes. The cooling bath was changed to ice cooling, allowing the reaction mixture to warm to 5° C. A mixture of 50 g of isovaleraldehyde and 50 ml of tetrahydrofuran was added dropwise. With stirring, the reaction mixture was warmed up to room temperature, after which stirring was continued for a further 5 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining crude 1,1,1,3,3-pentafluoro-4-hydroxy-2-heptanone. The crude product was combined with 50 g of water at room temperature, to which 100 g of 25 wt % sodium hydroxide aqueous solution was added. The mixture was stirred overnight at room temperature. With stirring, the mixture was slowly heated to 90° C. After cooling, the reaction mixture was extracted with n-hexane, with the hexane layer being discarded. The water layer was made acidic by adding 20 wt % hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate solution was dried and concentrated, obtaining 107 g (qualitative yield) of the target compound, 2,2-difluoro-3-hydroxy-5-methylhexanoic acid (Intermediate 1). This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@H:29]([C:33]([OH:35])=O)[CH:30]([CH3:32])[CH3:31])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:43][O:44][C:45](=[O:52])[CH2:46][NH:47][C:48](=[O:51])[CH2:49][NH2:50].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:43][O:44][C:45](=[O:52])[CH2:46][NH:47][C:48](=[O:51])[CH2:49][NH:50][C:33](=[O:35])[C@H:29]([CH:30]([CH3:32])[CH3:31])[NH:28][C:26](=[O:27])[C@H:22]([CH:23]([CH3:24])[CH3:25])[NH:21][C:19](=[O:20])[C@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(=O)O
Reactant: COC(=O)CNC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
N-tert-butoxycarbonyl O-benzyl L-seryl L-valine 17 (2.20 g, 4.46 mmol) and glycyl glycine methyl ester trifluoroacetate 21 (1.16 g, 4.44 mmol) were dissolved in CH2Cl2 (15 mL). N,N-diisopropylethyl amine (0.57 g, 4.4 mmol) and HOBt hydrate (0.68 g, 4.4 mmol) were added and the solution cooled to 0° C. EDC hydrochloride (0.94 g, 4.9 mmol) was added slowly together with 5 mL CH2Cl2. The reaction mixture was stirred for 1 h 30 min at 0° C. after which the icebath was removed. The mixture was stirred for an additional 23 hours before the volume was increased by addition of CH2Cl2 (20 mL). The solution was washed with 2 M aqueous H2SO4 (3×30 mL), 7.5% (w/w) aqueous K2CO3 (3×30 mL) and saturated brine (30 mL). The volume of the solution was increased, the solution dried with anhydrous MgSO4 and the solvent evaporated affording an off-white solid (2.14 g, 78%); δH (300 MHz; d6-DMSO) 8.25-8.20 (2H, m, NH(Gly1)/NH(Gly2)), 7.93 (1H, d, J 8, NH(Valx)), 7.70 (1H, d, J 9, NH(Valy)), 7.35-7.25 (5H, m, Ph), 7.06 (1H, d, J 8, NH(Ser(Bn))), 4.47 (2H, s, CH2Ph), 4.32-4.23 (2H, m, CαH(Ser(Bn))/CαH(Val)), 4.11 (1H, dd, J, CαH(Val)), 3.86 (2H, m, CαH2(Gly)), 3.75 (2H, d, J 6, CαHH(Gly)), 3.62 (3H, s, OCH3), 3.60-3.53 (2H, m, CH2), 2.01-1.88 (2H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 0.85-0.78 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.1, 170.9, 170.1, 169.6, 169.1, 155.2, 138.1, 128.0, 127.4, 127.3, 78.2, 71.9, 69.8, 58.1, 57.2, 54.5, 51.6, 41.6, 40.5, 30.8, 30.1, 28.1, 19.1, 18.2, 17.8; m/z (ESI) 644.3268 ([M+Na]+; C30H47N5O9Na requires 644.3271)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[S:38]1[CH:42]=[C:41]([CH2:43][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:43]\[C:41]4[N:40]=[CH:39][S:38][CH:42]=4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.3 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.27 g), potassium carbonate (0.44 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-4-[(Z)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.40 g, yield 34%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:31][CH2:28][CH:29]=[CH2:30])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C=CCN
Solvent: CC#N
Product: C=CCNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), prop-2-en-1-amine (0.5 ml) and ACN (2.5 ml) was heated under microwave radiation at 120° C. for 20 min. MS m/z (rel. intensity, 70 eV) 301 (M+, 2), 71 (5) 70 (bp), 69 (4) 68 (5).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=2)[NH:7][CH:6]=1)[CH3:4].C[N:20](C=O)C>>[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:15]([F:18])([F:16])[F:17])[CH:12]=2)[N:7]([NH2:20])[CH:6]=1)[CH3:4]
Reactant: CCc1c[nH]c2ccc(OC(F)(F)F)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(N)c2ccc(OC(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A suspension of NaH (7.9 g, 197 mmol, 60% in mineral oil) in DMF (60 mL) at 0° C. is treated with 3-ethyl-5-trifluoromethoxy-1H-indole (3 g, 13.1 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (7.4 g, 65.5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice and filtered through a pad of Celite. The filtrate is extracted with heptane (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-30% EtOAc in heptane to afford 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (2.05 g, 64%). MS: 245 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.37 (m, 2H), 7.11 (m, 1H), 7.00 (s, 1H), 4.72 (s, NH2, 2H), 2.73 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]=[C:10]=[O:11])=[C:4]([F:12])[CH:3]=1.[NH:13]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:14]1[C:15](O)=[O:16].[OH-].[Na+]>ClC1C=CC=CC=1.O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:15](=[O:16])[CH:14]3[CH2:18][CH2:19][CH2:20][CH2:21][N:13]3[C:10]2=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C=Nc1cc(O)c(Br)cc1F
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C1C2CCCCN2C(=O)N1c1cc(O)c(Br)cc1F
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
4-Bromo-2-fluoro-5-hydroxyphenyl isocyanate (3 g) was dissolved in chlorobenzene (5 ml), and a solution of pipecolic acid (1.7 g) and sodium hydroxide (0.56 g) in water (5 ml) was added thereto, followed by stirring at room temperature (ca. 20° C.) overnight. The aqueous layer was washed with ether, made acidic with an aqueous hydrochloric acid solution and heated under reflux for 2 hours. After allowed to cool, the resulting mixture was extracted with methylene chloride (300 ml). The extract was washed with sodium bicarbonate solution, dried and concentrated. The residue was recrystallized from ether to give 1.75 g of 2-(4-bromo-2-fluoro-5-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3(2H,8aH)-dione. M.P., 196°-199° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=O)[CH:12]=[C:11]2[CH3:19]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([Cl:3])[CH:12]=[C:11]2[CH3:19]
Reactant: COc1ccc2[nH]c(=O)cc(C)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)cc(C)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A 1-liter, four necked round bottom flask equipped with a mechanical stirrer, thermowatch, and condenser was charged with 630 grams (383 ml) of phosphorous oxychloride. The solution was heated to 50° C. and 6-methoxy-4-methyl-2-quinolone (2) (164.5 g, 0.87 moles) was added over 20 minutes. The reaction mixture was heated to reflux and held there for 2 hours. The hot reaction mixture was slowly poured into ice water (2.5 liters) and the resulting solution cooled to 30° C. The product was removed by suction filtration, washed with water and air dried to yield the title compound 156 g (86.4%); mp 144-145° C. (Lit2 mp 143.5-144.5° C.);
Reaction SMILES: C1C([N+]([O-])=O)=CC=C([Cl-][C:11]([O-])=[O:12])C=1.[CH:14]1([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:14]1([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:11]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:12])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: OC1CNC1
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.6 %

Procedure:
To a stirred RT solution of 4-nitrophenylchloroformate (2.63 g, 13.05 mmol) in DCM (10 ml) was added drop wise a solution of 1-cyclobutyl-1,4-diazepane (1.83 g, 11.86 mmol) and pyridine (1.03 g, 13.05 mmol) in DCM (2 ml). The resulting mixture was stirred at RT for approximately 3 days. The solvent was evaporated in vacuo and the residue dissolved in MeOH/IPA (1:3, 40 ml). Azetidin-3-ol hydrochloride (1.3 g, 11.86 mmol) and DIPEA (3.37 g, 26.1 mmol) were added and the resulting mixture was heated to reflux (˜90° C.) overnight. After cooling to RT, the solvent was evaporated and the residue partitioned between DCM (40 ml) and 2M K2CO3 aq (20 ml). The organic layer was separated and the aq. phase re-extracted with DCM (20 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as yellow solid (1.16 g, 39%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=O)[NH:8][C:4]=2[CH:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:7]1[N:6]([CH3:10])[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[N:8]=1
Reactant: Cn1c(=O)[nH]c2cc(F)ccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cn1c(Cl)nc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.9 g 5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one are suspended in 80 ml phosphorus oxychloride and the reaction mixture is stirred for 2 hours at reflux temperature. 50 ml diethylaniline are added. The reaction mixture is stirred for a further 10 minutes at reflux temperature and ice water is slowly added thereto. The product is extracted with dichloromethane and purified by chromatography (silica gel, cyclohexane, methylene chloride/acetone 20/1). 1.4 g product are obtained in the form of a solid. M.p.=138-141° C.