Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH:27]([CH3:29])[CH3:28])=[C:20](C(OCC)=O)[N:21]=4)=[C:13]([NH:30][CH:31]([CH3:33])[CH3:32])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C[Mg]Br>O1CCCC1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH:27]([CH3:29])[CH3:28])=[C:20]([C:19]([OH:18])([CH3:27])[CH3:20])[N:21]=4)=[C:13]([NH:30][CH:31]([CH3:33])[CH3:32])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C(C)C
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(C)(C)O)c(C(C)C)o1
Temperature: 25 °C

Procedure:
To a solution ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate (29) (150 mg, 0.34 mmol) in dry Tetrahydrofuran (10 mL) was added methyl magnesium bromide (2.132 mmol) (3.0 M in diethyl ether) at −78° C. Reaction mixture was allowed to warm up to 25° C. over 2 h. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated aqueous NH4Cl solution dropwise. Extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated to get the crude product, which was purified by flash column using ethyl acetate/hexanes as eluent to furnish 2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)propan 2-ol. 1H NMR: 400 MHz, DMSO-d6: δ 1.26-1.27 (m, 13H), 1.48 (s, 6H), 3.63-3.71 (m, 2H), 5.06 (s, 1H), 6.13 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.28 (d, J=6.80 Hz, 1H), 8.51 (s, 1H), 8.75 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.28 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.842 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.608 min; Purity: 97.8%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (265 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 64 mg of 182. MS (Q1) 485.2 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].O[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:23][CH:22]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1)OCC
Temperature: 25 °C
Yield: 65.3 %

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) (0.71 g; 2.97 mmole) dissolved in dichloromethane (5 ml) was added to a mixture of N-[4-(2-hydroxyethyl)phenyl]isobutyramide (0.5 g; 2.47 mmole), azodicarbonyl dipiperidine (0.75 g; 2.97 mmole) and triphenylphosphine (0.78 g; 2.97 mmole) in dichloromethane (15 ml). After stirring at room temperature over night the reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using heptane:ethyl acetate (gradient 3:1 to 1:1) as eluant to give 0.69 g (yield 65%) of 2-ethoxy-3-{4-[2-(4-isobutyrylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [ClH:1].Cl.C1([C:9]2[O:13][C:12]([CH:14]=[C:15]3[CH2:20][CH2:19][CH2:18][N:17]=[C:16]3[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:10]=2)C=CC=CC=1.[F:27][C:28]1[C:29]([C:35]([F:38])([F:37])[F:36])=[C:30](Br)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[F:27][C:28]1[C:29]([C:35]([F:38])([F:37])[F:36])=[C:30]([C:9]2[O:13][C:12]([CH:14]=[C:15]3[CH2:20][CH2:19][CH2:18][N:17]=[C:16]3[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:10]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: C(=C1CCCN=C1c1cccnc1)c1ccc(-c2ccccc2)o1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2ccc(C=C3CCCN=C3c3cccnc3)o2)c1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
Intermediate 5 (190 mg, 0.67 mmol) (prepared as described in Example 35) was dissolved into a 1:1 mixture of toluene (20 mL) and 1,4-dioxane (10 mL) in a reaction vessel. 3-Fluoro-2-(trifluoromethyl)bromobenzene (326 mg, 1.34 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol), and 2 M Na2CO3(aq) (670 μL, 1.34 mmol) were added and the reaction vessel flushed with N2 and sealed. The reaction mixture was heated to 110° C. with stirring overnight. The reaction was then cooled to room temperature, filtered through Celite®, and the filtrate concentrated under reduced pressure. The recovered material was then treated with water and extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was then eluted through a 20 gram column of silica gel with 98:2:0.2 CH2Cl2:MeOH:NH4OH (1 liter). The material recovered from this column was eluted through a second 20 gram column of silica gel with an 8.5:7:7:0.5:0.05 (685 mL) and with 7:7:7:1:0.1 (440 mL) Hexane:MtBE:CH2Cl2: MeOH:NH4OH step gradient. The recovered material was dissolved into MeOH and treated with 2 eq. of 6 N HCl(aq). This solution was then concentrated under reduced pressure and the recovered material re-crystallized from a mixture of hot ethanol and isopropanol. The crystals were recovered by vacuum filtration and washed with a 20% solution of isopropanol in hexane, and then with ether, then dried under vacuum giving 29 mg (9%) of a golden yellow solid. LC-MS: RT=5.88 min, [M+H]+=401.0.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1.[H-].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:11]=[C:10]([CH:9]=[CH:8][C:6]=1[OH:7])[O:12][C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 32.5 %

Procedure:
In a similar manner to that described in Reference Example 6 a reaction was carried out using t-butylhydroquinone (1.66 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=4/1 to give t-butyl N-[5-(3-t-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.35 g), of which Rf value was 0.45 in thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=3/1 and t-butyl N-[5-(2-t-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.11 g), of which Rf value was 0.35 in thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=3/1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14](C)=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1C)[CH:2]=[CH2:3].OC1C=CC(C#N)=CC=1>>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1C
Agent: N#Cc1ccc(O)cc1
Product: C=CCOc1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to 4-allyloxy-N-hydroxy-3,5-dimethyl-benzamidine by allylating commercially available 4-hydroxy-benzonitrile followed by transforming the nitrile to the hydroxyamidine; LC-MS: tR=0.59 min, [M+1]+=193.58.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 68.8 %

Procedure:
First, 10.16 g (145 mmol) of crotonaldehyde and 10.09 g (60.4 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) were added as the solvent, and the mixture was heated under reflux for 15 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried in vacuo for 2 hours to give 9.11 g of 2-benzenesulfonyl-pyridine as colorless crystals (purity of 90%, yield of 62% based on benzenesulfonyl cyanide).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]([F:19])([F:18])[CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[F:13][C:14]([F:19])([F:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: OCCC(F)(F)F
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(OCCC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
6-Hydroxy-1-tetralone (3.5 g, 21.6 mmol), 3,3,3-trifluoro-1-propanol (4.93 g, 43.2 mmol) and triphenylphosphine (11.3 g, 43.2 mmol) were combined in THF (80 mL). DIAD (8.7 g, 43.2 mmol) was added, and the reaction stirred overnight at rt. The solution was diluted with EtOAc (100 mL) and washed with brine. Organics were dried (MgSO4) and concentrated. Purification by silica gel chromatography (10-50% EtOAc/hexanes) gave 2.93 g (53%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, 1H, J=8.7 Hz), 6.82 (dd, 1H, J=8.7, 2.5 Hz), 6.71 (d, 1H, J=2.4 Hz), 4.25 (t, 2H, J=6.6 Hz), 2.93 (t, 2H, J=6.1 Hz), 2.59-2.71 (m, 4H), 2.08-2.16 (m, 2H). [M+H] calc'd for C13H13F3O2, 259. Found 259.
Reaction SMILES: O[N:2]1[CH:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:3]1.[ClH:23].[O:24]1CCOCC1>C(OCC)(=O)C>[ClH:23].[OH:24][CH:9]([CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH2:8][O:7][C:6]1[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:3][N:2]=1
Reactant: C1COCCO1
Reactant: ON1OC(c2ccccc2)=CC1OCCCN1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(COc1cc(-c2ccccc2)on1)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5.00 g of 3-(2-hydroxy-3-morpholinopropoxy-5-phenylisoxazole dissolved in ethyl acetate (200 ml) was added a 4N HCl/dioxane solution (5.0 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to afford 5.21 g of the title compound with melting point 149°-150° C. as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].O[CH2:27][CH:28]1CC1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:28][CH2:27]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: OCC1CC1
Agent: [C-]#N
Agent: [K+]
Product: CN1Cc2c(C(=O)OCC3CC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
A mixture of 5.0 g (15.6 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 20 ml of hydroxymethyl-cyclopropane and 0.5 g of powdered potassium cyanide is heated to 130° for 18 hours, about 1 ml of solvent being distilled off after 1.3 hours and after 6 hours. The mixture is subseqently evaporated in vacuo and the residue is partitioned between chloroform and water. The chloroform phase is washed three times with water, dried over magnesium sulphate and evaporated. The material obtained is chromatographed on silica gel while eluting with ethyl acetate and subsequently crystallized from ethyl acetate. There is obtained cyclopropylmethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 194°-195°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=[C:5]2[C:15]([O:17]C(C)(C)C)=[O:16].Cl>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=[C:5]2[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)c1cn(S(C)(=O)=O)c2ccc(F)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1cc(C(=O)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate (150 mg, 0.479 mmol) and conc. HCl (0.2 ml, 2.394 mmol) in EtOAc (10 ml) was stirred at RT for 2 h. The mixture was then partially concentrated, and the resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to afford the title compound as a white solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH2:34][CH2:35][CH:36]([F:38])[F:37])([CH2:29][CH2:30][CH:31]([F:33])[F:32])[C:24]([O:26]CC)=[O:25])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH2:29][CH2:30][CH:31]([F:33])[F:32])([CH2:34][CH2:35][CH:36]([F:37])[F:38])[C:24]([OH:26])=[O:25])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C(CCC(F)F)(CCC(F)F)C(=O)O)ccc2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
500 mg of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoate are dissolved in 7 ml of tetrahydrofuran, and 5 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 50° C. for 4 h and subsequently evaporated in vacuo. The mixture is then adjusted to pH2 using 3 ml of 25% hydrochloric acid with ice-cooling, with yellow crystals precipitating. The precipitate obtained is filtered off and dried in vacuo. Yield: 170 mg (36%) of 2-[2-2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoic acid;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, methanesulfonyl chloride (7.6 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 14.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].OC[C:9]1([OH:20])[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:10]1>O1CCOCC1.O>[O:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=[CH:15][C:9](=[O:20])[CH2:10]1
Reactant: OCC1(O)C=Cc2ccccc2OC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1C=Cc2ccccc2OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
4×28.5 mg (0.55 mmol) of sodium periodate are added in four equal portions over 30 minutes to 106 mg (0.55 mmol) of 3-(hydroxymethyl)-2,3-dihydro-1-benzoxepin-3-ol, prepared according to example 24, in solution in 3 ml of a 3/7 dioxane/water mixture. After stirring at ambient temperature for 2 hours, the medium is filtered through celite and the solid is discarded. After the usual extracting and washing treatments, purification by chromatography on silica gel (dichloromethane) provides 61 mg (70%) of 1-benzoxepin-3(2H)-one; 1H NMR (300 MHz, CDCl3): 7.45–7.35 (m, 2H), 7.15–7.25 (m, 3H), 6.38 (d, J=8.7 Hz, 1H), 4.55 (s, 2H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
To 10.4 g of ethyl acetoacetate were added 15 g of 1,2-dibromoethane, 23 g of potassium carbonate, and 150 ml of N,N-dimethylformamide (DMF), and the mixture was stirred at room temperature for 2 days. Any insoluble matter was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting pale yellow oily substance was subjected to distillation under reduced pressure to obtain 7.5 g of ethyl 1-acetyl-1-cyclopropanecarboxylate having a boiling point of 70° to 71° C./2 to 3 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:22](Cl)([Cl:24])=[O:23]>C(OCC)C>[C:9]1([N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:22]([Cl:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1N=C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccccc1N(C(=O)Cl)C1=CCCCC1

Procedure:
187 parts of cyclohexanone-o-methylphenylimine and 120 parts of triethylamine are added in portions and at 0° to 10° C. to a solution of 120 parts of phosgene in 400 parts of diethyl ether over a period of 1 hour in a manner analogous to that employed in Example 10. The mixture is stirred for another hour. The end product is then isolated analogously to Example 10. 216 parts (87% of the theory) of N-1-cyclohexenyl-N-o-methylphenylcarbamyl chloride is obtained having a boiling point of 132° C. at 0.3 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>C(#N)C>[CH2:13]([NH:15][C:16](=[S:17])[NH:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1)[CH3:14]
Reactant: CCN=C=S
Reactant: N#CCCCCn1ncc(N)n1
Solvent: CC#N
Product: CCNC(=S)Nc1cnn(CCCCC#N)n1
Reaction time: 60 h

Procedure:
A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (1.65 g.) in acetonitrile (6 ml.) was treated with ethylisothiocyanate (0.87 g.) and the solution stirred for 2.5 days then heated under reflux for 4.5 hours. Evaporation of the solvent gave 5-[4-(3-ethylthioureido)-1,2,3-triazol-2-yl]valeronitrile.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[O:17][C:16](=O)[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[NH4+:24]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[NH:24][C:16](=[O:17])[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(C(F)(F)F)cc1)COC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)COCC2c1ccc(C(F)(F)F)cc1

Procedure:
8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Z(3)) was reacted as described in Intermediate X(4) with ammonium hydroxide to give 8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione (Intermediate Z(4)). LC-MS (M−H)+=313.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Br)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(Br)noc1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Product: CCOC(=O)c1c(N2CCCC2)noc1C
Temperature: 180 °C
Yield: 26.1 %

Procedure:
A mixture containing 3-bromo-5-methyl-isoxazole-4-carboxylic acid ethyl ester (5.0 g, 18.8 mmol), pyrrolidine (13.37 g, 188 mmol) and BEMP (10.53 g, 37.6 mmol) was heated in the microwave at 180° C. for 10 min. The mixture was then extracted with ethyl acetate, dried over potassium sulphate, filtered and evaporated. Purification by chromatography (silica, ethyl acetate:methanol 1:9 to 3:7) afforded the title compound (1.1 g, 21%) as a yellow oil. MS: m/e=225.3 [M]+.