Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](P(N(C)C)(N(C)C)=O)[CH3:3].CNC.CO[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:23]=2)[CH:18]=1>C1C=CC=CC=1>[CH3:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([C:22]1[CH:21]=[CH:20][C:19]2[CH:18]=[C:17]([N:2]([CH3:3])[CH3:1])[CH:26]=[CH:25][C:24]=2[CH:23]=1)=[O:39]
Reactant: CCCCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CNC
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)c1ccc2cc(N(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Li (0.5 g, 70 mmol) was added to HMPA (20 ml) and benzene (30 ml), and then dimethylamine (3.5 g, 78 mmol) was added dropwise thereto. The mixture was violently stirred for one hour. To the resulting mixture was added 2-methoxy-6-dodecanoylnaphthalene (7.3 g, 22 mmol) prepared in Comparative Example 1-(1) all at one time. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-water, extracted with ether, evaporated to remove the solvents, and recrystallized from ethanol to give Laurdan (5.1 g, yield: 66%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:49][C:50]([F:56])([F:55])[S:51](Cl)(=[O:53])=[O:52]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:51]([C:50]([F:56])([F:55])[F:49])(=[O:53])=[O:52])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C(F)(F)F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 49 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added trifluoromethylsulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 49% yield.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[F:36])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C=O.CC(O)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH:10]5[CH2:9][N:8]([CH3:6])[CH2:11]5)=[C:14]([F:36])[CH:15]=4)[CH:24]=[CH:23][C:22]=3[CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (0.491 g, 0.932 mmol) in CH2Cl2 (10 mL) and treat with TFA (3 mL), with stirring at RT for 2 h. Remove the excess reagent and solvent in vacuo. Dissolve the crude material in CH3OH (15 mL), treat with formaldehyde (0.28 mL, 3.71 mmol, 37% aqueous solution), HOAc (0.21 mL, 3.71 mmol) and NaBH3CN (0.233 g, 3.71 mmol). Stir the mixture at RT for 30 min followed by reflux for 4 h. Quench the mixture with saturated NH4Cl solution (10 mL). Dilute with water (10 mL) and saturated NaHCO3 (30 mL). Extract with EtOAc (3×50 mL). Dry the combined organic layers with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 1% Et3N, 10% CH3OH/CHCl3 to give 2-(4-chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one (0.3012 g, 0.683 mmol, 74%). Dissolve the free base (0.152 g, 344.7 μmoles) in CH2Cl2 (5 mL) and CH3OH (0.5 mL). Treat the mixture with 1.0 M HCl in EtOH (344.7 μmoles; 344.7 μL). Add Et2O (50 mL), filter, and wash with Et2O (2×20 mL). Dry in a vacuum oven at RT for 2 days to give 0.14 g (83%) of the title compound. LC-MS/ES m/z (35Cl) 441.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:16]([F:18])([F:19])[F:17])[C:6]=2[CH:5]=[C:4]([O:20][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(9R)-4-Chloro-9-(trifluoromethyl)-9H-fluorene-2,9-diol (200 mg) obtained in step 10 of example 1 was dissolved in N,N-dimethylformamide (2 ml), potassium carbonate (185 mg) and ethyl 4-bromobutyrate (105 μl) were added, and the mixture was stirred at room temperature for 7 hr. To the reaction mixture was added water, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with water (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture at a mixing ratio 5:1 (hexane:ethyl acetate), then successively with a mixture at a mixing ratio 3:1, and further with a mixture at a mixing ratio 2:1) to give the title compound (197 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[C:17](Cl)=[CH:18][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[N:20][CH:21]=2)=[O:14])=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]2[O:14][C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:20]=[CH:21][C:16]=3[N:15]=2)=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCc3ccccc3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 3 h
Yield: 29.4 %

Procedure:
A suspension of tert-butyl ((2S)-1-((5-((4-(benzyloxy)-3-fluorobenzoyl)amino)-4-chloropyridin-2-yl)oxy)propan-2-yl)carbamate (6.28 g), potassium carbonate (3.28 g) and copper(I) iodide (226 mg) in DMF (40 mL) was stirred at 160° C. for 3 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.72 g).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]=[CH:19][N:20]([C@@H:36]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]3[OH:38])[C:21]=2[NH:22][C:23]([NH:25]C(OCC2C=CC=CC=2)=O)=[O:24])=[O:16])C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1.C(O)C.[Pd]>[NH2:25][C:23]([NH:22][C:21]1[N:20]([C@@H:36]2[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]2[OH:38])[CH:19]=[N:18][C:17]=1[C:15]([OH:16])=[O:14])=[O:24]
Reactant: O=C(NC(=O)OCc1ccccc1)Nc1c(C(=O)OC(c2ccccc2)c2ccccc2)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)Nc1c(C(=O)O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
5-[[[[(phenylmethoxy)carbonyl]amino]carbonyl]amino]-1-(β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid diphenylmethyl ester (1.76 g, 2.9 mmol) was dissolved in the mixture of DMF (50 mL), THF (20 mL) and ethanol (30 mL) and mixed with 10% palladium on charcoal. The mixture was hydrogenated at 50 psig pressure for 2 h. The catalyst was removed by filtration through Celite, and washed extensively with DMF and ethanol. Combined washing and filtrate was concentrated under reduced pressure to dryness. Residue was dissolved in 30% aqueous ethanol and filtered through a C18-Sep-Pak to remove the last traces of catalyst. This eluate was concentrated to dryness and partitioned between water (100 mL) and ether (2×100 mL). The aqueous layer was concentrated to dryness, redissolved in water and evaporated again and pumped under high vacuum to give 5-[[(amino)carbonyl]amino]-1-(β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid as a colorless glass: yield 0.64 g (73%); IR (KBr) 3340, 1692 cm -1 ; NMR (Me2SO-d6) δ3.72-3.53 (m, 2), 3.84 (d, 1, J=4.3 Hz), 4.05 (s, 1), 4.14 (s, 1), 5.05 (s, 1), 5.11 (s, 1), 5.34 (s, 1), 5.50 (d, 1, J=4.3 Hz), 6.28 (s, 2), 7.92 (s, 1), 8.07 (s, 1); UV max (H2O) 215 nm (ε5800).
Reaction SMILES: [F:1][C:2]([F:31])([CH3:30])[CH2:3][N:4]([CH2:27][CH2:28][OH:29])[C:5]([C:7]1[C:11](O)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:8]=[C:7]3[C:11]=2[O:29][CH2:28][CH2:27][N:4]([CH2:3][C:2]([F:1])([F:31])[CH3:30])[C:5]3=[O:6])=[CH:14][CH:15]=1
Reactant: CC(F)(F)CN(CCO)C(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(F)(F)CN1CCOc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)4-hydroxy-1H-pyrazole-3-carboxylic acid (2,2-difluoro-propyl)-(2-hydroxy-ethyl)-amide I-3d (10 g, 21 mmol), triphenyl phosphine (8.4 g, 31.5 mmol) in toluene (210 ml) was added 1,1′-(azodicarbonyl)dipiperidine (8.0 g, 31.5 mmol). After 18 hours, 20% ethyl acetate:hexanes (210 ml) was added, the mixture was stirred at ambient temperature for 1 hour and filtered. The filtrate was concentrated in vacuo and the resulting oil was chromatographed on silica gel (20–70% ethyl acetate:hexanes) to afford the title compound (2A-1) as a solid, 7.8 g. 1H NMR in CDCl3 (ppm) δ 7.53–7.50 (m, 1H), 7.38–7.33 (m, 3H), 7.24–7.21 (m, 2H), 7.16–7.13 (m, 2H), 4.45 (br s, 2H), 4.02 (t, 2H), 3.90 (br s, 2H), 1.69 (t, 3H); ms (LCMS) m/z=452.2 (M+1). Combustion analysis calculated for: C: 55.77%; H: 3.79%; N: 9.29%. Found: C: 55.69%; H: 3.52%; N: 9.13%.
Reaction SMILES: CC[O:3][C:4]([C@@H:6](O)[CH3:7])=O.[C:9]([OH:14])(=[O:13])[C@H:10]([CH3:12])[OH:11].C(O)(=O)C(C)O>>[CH3:12][C@@H:10]1[O:11][C:4](=[O:3])[C@H:6]([CH3:7])[O:14][C:9]1=[O:13]
Reactant: C[C@H](O)C(=O)O
Reactant: CCOC(=O)[C@H](C)O
Agent: CC(O)C(=O)O
Product: C[C@@H]1OC(=O)[C@H](C)OC1=O

Procedure:
The reaction was performed in the same manner as in Example 1 to produce lactide, except that a mixture containing L-ethyl lactate with L-lactic acid and an oligomer of lactic acid which were 10% by weight with respect to L-ethyl lactate.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:4].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O.CCCCCC>[Si:19]([O:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: C#CC(O)CCCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 3-hydroxyoct-1-yne (see Preparation 3.A.) (2.89 g, 0.02 mol), in N,N-dimethylformamide (DMF), cooled to 0° C., was added imidazole (2.1 g), followed by tert-butyldimethylchlorosilane (3.1 g, 0.02 mol), and the mixture was stirred for 3 h. Water (80 ml) and hexane (80 ml) were added; the organic layer was separated and combined with 2×80 ml of hexane extractions of the aqueous layer. The solvent was removed (in vacuo), after drying over sodium sulfate, to give a crude residue (4.3 g) which was chromatographed on silica gel (80 g), eluting with ethyl acetate-hexane (2:1, v/v) to afford 3-tert-butyldimethylsilyloxyoct-1-yne. JACS, 94, 6190, (1972).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[O:6][CH:7]=1.[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([C:26](O)=[O:27])[C:14]=2[CH:13]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH:8][C:26]([CH:15]2[C:14]3[CH:13]=[C:12]([Cl:11])[CH:25]=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:27])[O:6][CH:7]=1
Reactant: Nc1nc(C(F)(F)F)co1
Reactant: O=C(O)C1c2ccccc2Oc2ccc(Cl)cc21
Product: O=C(Nc1nc(C(F)(F)F)co1)C1c2ccccc2Oc2ccc(Cl)cc21

Procedure:
The title compound, white solid, m.p. 235° C. and MS: m/e=395.2, 397.2 (M+H+) is prepared in accordance with the general method of example 3c from 4-trifluoromethyl-oxazol-2-ylamine and (RS)-2-chloro-9H-xanthene-9-carboxylic acid (CAS:[188027-67-0]).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[N:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:5])[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH:15]=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[N:8][C:7]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
A mixture of 0.080 g (0.2 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1b), 2 mL of dichloromethane and 0.027 mL (0.24 mmole) of 1-methyl-piperizine was stirred at ambient temperature for 10 minutes, then 0.064 g (0.3 mmole) of sodium triacetoxyborohydride was added. The mixture was stirred at ambient temperature for 2 hours and was then diluted with 10 mL of dichloromethane. The mixture was washed with 3 mL of saturated sodium bicarbonate. The aqueous layer was extracted twice with 5 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-5:95) to give 0.066 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1c) as an orange solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])#[N:29]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:23][CH2:24][N:25]([S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:28]#[N:29])(=[O:38])=[O:37])[CH2:26][CH2:27]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C#N)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)-2,3-diazaspiro[4.4]non-3-en-1-one hydrochloride (compound B10*HCl) and 2-cyanobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]2[CH:8]=[C:9](SC)[CH:10]=[CH:11][C:5]=2[N:4]([CH2:14][CH:15]=[CH2:16])[S:3]1(=[O:18])=[O:17].O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]C(C)=O>O>[CH3:19][C:2]1([CH3:1])[CH2:7][C:6]2[CH:8]=[C:9]([CH:26]=[S:22](=[O:24])=[O:21])[CH:10]=[CH:11][C:5]=2[N:4]([CH2:14][CH:15]=[CH2:16])[S:3]1(=[O:17])=[O:18]
Reactant: O=S([O-])OO
Reactant: C=CCN1c2ccc(SC)cc2CC(C)(C)S1(=O)=O
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: C=CCN1c2ccc(C=S(=O)=O)cc2CC(C)(C)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-3,3-dimethyl-6-methylthio-1-(prop-2-en-1-yl)-1H-2,1-benzothiazine 2,2-dioxide (1.6 g;0.00539 mol) was dissolved in acetone (50 mL) and oxone (7.29 g; 0.01185 mol) in water (20 mL) was added. The solution went opaque and was stirred for 30 min at room temperature. The acetone was removed on the rotary and water and ethyl acetate were added. The product was extracted with ethyl acetate (2×100 mL) and the organic extracts washed with water (2×100 mL). After drying, filtering and removal of solvent, a solid was isolated (1.2 g; 68%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][C:31]4[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=4[CH3:39])[CH:23]=3)[CH:14]=2)[N:9]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:18]([N:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][C:31]4[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=4[CH3:39])[CH:23]=3)[CH:14]=2)[N:9]=[C:8]1[NH2:7])[CH2:19][CH3:20]
Reactant: CCCN1Cc2cc(Oc3cccc(CNCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN1Cc2cc(Oc3cccc(CNCc4c(C)cc(C)cc4C)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-propyl-6-{3-[(2,4,6-trimethyl-benzylamino)-methyl]-phenoxy}-3,4-dihydro-quinazolin-2-yl)-carbamic acid tert-butyl ester (0.00041 mol) in trifluoroacetic acid (1 mL) and DCM (10 mL) was stirred overnight at room temperature and the solvent was evaporated. The obtained residue was decomposed in diisopropyl ether/CH3CN, then the desired product was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.N>ClCCl>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:32])([F:13])[F:31])[N:20]=2)=[CH:27][CH:26]=1
Reactant: NCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cccc2c(NCCc3ccc(Oc4cccc(C(F)(F)F)n4)cc3)ccnc12
Yield: 58.5 %

Procedure:
A mixture of 4-chloro-8-fluoroquinoline (1.81 g, 0.01 mol), and 2-(4-(6-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) was heated at 180°-190° C. for two hours and allowed to cool to a glass. Dichloromethane (50 mL) and concentrated ammonia solution (50 mL) were added, and the mixture was stirred until the glass dissolved. The organic phase was washed with 0.5M sodium hydroxide solution and water, and was dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 157° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]#[CH:25])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.O>CN(C=O)C.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.[Cu]I>[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]#[C:25][C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Brc1cnc2cccnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C#Cc2cnc3cccnn23)C1
Yield: 59.7 %

Procedure:
A solution of 3-bromoimidazo[1,2-b]pyridazine (0.40 g, 2 mmol), 1-BOC-3-ethynylpiperidine (0.55 g, 2.6 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (29 mg, 0.15 mmol), and DIPEA (0.39 g, 3 mmol) in DMF (20 mL) was stirred at 80° C. under Are for 6 hrs. The mixture was poured into 100 mL water, extracted with EtOAc (60 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The crude product was purified by chromatography on silica gel (PE/EtOAc 7:3 to 3:2) to give 0.39 g product as yellow oil (60.0%). 1H NMR (300 MHz, CDCl3) δ: 8.50 (1H, d, J=4.2 Hz), 7.98-8.08 (2H, m), 7.13-7.17 (1H, dd, J=4.5 and 8.7 Hz), 4.09 (1H, brs), 3.76-3.82 (1H, m), 3.19 (1H, brs), 3.02-3.09 (1H, m), 2.81-2.88 (1H, m), 2.32 (1H, brs), 2.11-2.15 (1H, m), 1.67-1.81 (2H, m), 1.46 (9H, s). LCMS: m/z [M+H]+ 327.2112.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:16]=[C:17]([CH:22]2[NH:27][C:26]([O:28][CH3:29])=[N:25][C:24]([CH3:30])=[C:23]2[C:31]([O:33][CH3:34])=[O:32])[CH:18]=[CH:19][C:20]=1[F:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH:22]2[N:27]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:26]([O:28][CH3:29])=[N:25][C:24]([CH3:30])=[C:23]2[C:31]([O:33][CH3:34])=[O:32])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
4-Nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added to a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.46 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH2Cl2 (50 mL), at 0-5° C. and the mixture was then allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as white crystals (3.72, 85%): mp 172-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([OH:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)CC(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one (0.50 g, 0.0024 mol) in tetrahydrofuran (1 mL) was added to a suspension of lithium aluminum hydride (0.10 g, 0.0027 mol) in tetrahydrofuran (1 mL) cooled to 0° C. The mixture was stirred at 20° C. for 16 h. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5-methylcyclohexanol (0.40 g) as a mixture of four diastereoisomers (ratio 2.8:15.3:79.2:2.8).