Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[C:8]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:9][C:10]([S:21][CH3:22])=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])C>C1(C)C=CC=CC=1>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:23]1[C:8]2[N:9]=[C:10]([S:21][CH3:22])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:3]
Reactant: CCOC(=O)/C=C/c1c(Nc2c(F)cccc2F)nc(SC)nc1-c1ccc(F)cc1C
Solvent: Cc1ccccc1
Product: CSc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 220 °C
Yield: 97.6 %

Procedure:
(E)-3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester (8.1 g, 17.6 mmol) was dissolved in 50 mL of anhydrous toluene. Reaction mixture was heated in a sealed tube at 220° C. for 48 h, toluene was evaporated and the yellow residue purified by Flash chromatography to give 7.1 g (96%) of 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 2.24 (s, 3H), 2.29 (s, 3H), 6.63 (d, 1H, J=9.6 Hz), 7.03-7.20 (m, 4H), 7.25 (m, 1H), 7.51 (m, 2H); LC MS (m/e)=414 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1n[nH]cc1NC1CCCCC1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (200 mg; 1 mmol) and cyclohexanone (107 mg; 1.1 mmol) in dichloromethane (10 ml) were added 3 Å molecular sieves (1 g) and sodium triacetoxyborohydride (315 mg; 1.5 mmol), and the mixture was then stirred at room temperature over the weekend. The reaction mixture was filtered through Celite®, diluted with ethyl acetate, washed with brine, dried (MgSO4) and evaporated to give the 48 mg of the product as a grey gum. (LC/MS: Rt 2.95, [M+H]+ 285).
Reaction SMILES: O=[CH:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].Cl.[NH2:14][OH:15].N1C=CC=CC=1>CO>[OH:15][N:14]=[CH:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: C[C@H](C=NO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.4 %

Procedure:
A mixture of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 81.0 mmol), hydroxylamine hydrochloride (11.2 g, 81.0 mmol), pyridine (60 mL), MeOH (100 mL) was stirred at rt overnight. The solvent was then evaporated. To the residue was added water (100 mL) and the mixture was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography (petroleum ether: EtOAc, 4:1) to give (R)-tert-butyl 1-(hydroxyimino)propan-2-ylcarbamate (24.0 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 4.12 (m, 1H), 1.38 (s, 9H), 1.15 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH:15]=3)[N:10]([C:24](=[O:32])[NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:34]4[CH2:37][CH2:36][CH2:35]4)=[O:22])[CH:15]=3)[N:10]([C:24]([NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)=[O:32])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCCC(=O)O)cc12
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCCC(=O)N3CCC3)cc12

Procedure:
5-(1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)pentanoic acid and azetidine hydrochloride
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
1.95 g (6.3 mmol) of ethyl 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (30 mL), and 1.31 g (9.5 mmol) of potassium carbonate and 60 mL of water were added to this solution at room temperature. The resulting mixture was stirred for 3 hours at 50° C. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was dissolved in water. Concentrated hydrochloric acid was added to make the solution acidic, and the mixture was extracted with chloroform. The organic phase was dried, filtered, and concentrated, and thus 1.71 g (yield: 97%) of the title compound was obtained as colorless crystals.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH:15]2[CH2:16][CH:9]3[CH:10]([CH:14]2I)[O:11][C:12](=[O:13])[CH:8]13)=[O:6])#[N:2].O1CCCC1.OP([O-])(O)=O.[K+]>O.C(OCC)(=O)C.[Zn]>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[C@@H:15]2[CH2:16][C@@H:9]([CH:10]=[CH:14]2)[C@H:8]1[C:12]([OH:13])=[O:11])=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1C2CC3C(OC(=O)C31)C2I
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-N-(cyanomethyl)-6-iodo-2-oxohexahydro-2H-3,5-methanocyclopenta[b]furan-7-carboxamide (1.45 g, 4.18 mmol) was added tetrahydrofuran (10 mL) and zinc dust (11.0 g, 170 mmol). 1 M aqueous KH2PO4 (21 mL, 21 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate and filtered through Celite™ and the Celite™ was washed well with water and ethyl acetate. The product was extracted into ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution. The organics were dried with anhydrous sodium sulfate and then concentrated on a rotary evaporator to give (1S,2R,3R,4R)-3-{[(cyanomethyl)amino]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a faint-yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:36])([CH2:32][CH2:33][CH:34]=C)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]=[O+][O-]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:36][CH:34]([OH:37])[CH2:33][CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C=CCCC(O)(CCOCCCCCCCCCCCCCCCCCC)COCc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(O)O1
Temperature: 25 °C

Procedure:
6.15 g (12.3 mmol) of the compound prepared in (c) above in 100 ml of methylene chloride was treated with ozone at -60° C. After consumption of the olefin, 25 ml of dimethyl sulfide was added and the mixture allowed to warm to room temperature. The solvent was removed in vacuo and the crude product was purified on silica gel employing a mixture of petroleum ether and diethylether in a ratio of 7:3 as the eluent to yield a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(CNCc3ccccn3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with pyridin-2-ylmethylamine as described in Method A, Example 123 to give the title compound. MS: m/e=335 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:30])[C:20]([O:26][CH:27]([F:29])[F:28])=[CH:21][CH:22]=3)[C:17]2=[O:31])=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:19]1[C:20]([O:26][CH:27]([F:29])[F:28])=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:31])[N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:33])=[CH:12][C:13]=1[CH3:32])[CH2:25][CH2:24]2
Reactant: Cc1cc(C)c(CN2CCc3ccc(OC(F)F)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3ccc(OC(F)F)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (1i, 0.08 g, 0.169 mmol) in CH2Cl2 (10 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum to give a residue, which was dissolved in CH2Cl2 (20 mL) and then washed with sat. NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. TLC (EtOAc) to obtain the title compound (Example 1, 43.1 mg, 67%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.36-7.34 (m, 1H), 7.24-7.22 (m, 1H), 7.00-6.63 (m, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 3.51-3.48 (m, 2H), 2.90-2.87 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H); MS 382.9 [M+1].
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CCOCC>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([N:19]([O:20][CH3:21])[CH3:18])=[O:5]
Reactant: CNOC
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(C)(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A 100 mL flask was charged with 3,3,3-trifluoro-2,2-dimethylpropanoic acid (1.00 g, 6.41 mmol), methylene chloride (25 mL) and DMF (1 drop). The system was purged with nitrogen and cooled to 0° C. Oxalyl chloride (0.650 mL, 7.69 mmol) was added dropwise over about 1 minute and the reaction was stirred at 0° C. for 2 min, then allowed to warm to room temperature. After 4 hours, a solution of N,O-dimethylhydroxylamine hydrochloride (0.937 g, 9.61 mmol) and N,N-diisopropylethylamine (3.35 mL, 19.2 mmol) in methylene chloride (5 mL) was added to the resulting acid chloride and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ether (50 mL) and washed with 1 M NaH2PO4 (2×15 mL), saturated NaHCO3 (15 mL), dried (Na2SO4), filtered and evaporated to obtain the amide as an oil (1.38 g, quant.), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 3.70 (s, 3H), 3.21 (s, 3H), 1.50 (s, 6H); m/z=200.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][C:29](C)(C)C)=[O:27])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C1COCC1.O.O.CCOC(C)=O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][CH3:29])=[O:27])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-benzyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate (0.52 g, 1.15 mmol) in CH2Cl2 was added TFA (4 mL). The mixture was allowed to stir at room temperature for 2 h. The mixture was concentrated in vacuo to give a colorless oil which solidified on standing. This material was dissolved in THF-H2O and cooled to 0° C. Solid NaHCO3 (0.25 g, 3.00 mmol) was added followed by C1CO2Me (0.25 mL, 3.25 mmol). After stirring for 1.5 h the mixture was acidified to pH˜2 with 6N HCl and then poured into H2O-EtOAc. The layers were separated and the aq phase extracted 2× with EtOAc. The combined org layers were washed (H2O, brine), dried (Na2SO4), filtered, and concentrated in vacuo to give a colorless oil (505.8 mg, 111%, NMR suggested the presence of an unidentified impurity) which solidified while standing on the pump. The material was used as is without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H), 4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J=5.6, 14.7 Hz, 1H), 2.98 (dd, J=9.6, 14.7 Hz, 1H). LC-MS: Anal. Calcd. for C21H22N4O4: 394; found: 395 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.96 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=480.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17]Br)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C([Mg]Cl)=C.Cl[CH:24]([Mg]Cl)[CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].[Mg].ClCC(C)CCCC(C)CCCC(C)C>C1COCC1>[CH3:14][C:6]1[C:7]([OH:13])=[C:8]([CH3:12])[C:9]2[CH2:10][CH2:11][C@:2]([CH2:16][CH2:17][CH2:35][C@@H:33]([CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:28][CH2:27][CH2:26][CH:25]([CH3:37])[CH3:24])[CH3:36])[CH3:34])([CH3:1])[O:3][C:4]=2[C:5]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Reactant: CC(C)CCCC(C)CCCC(C)C(Cl)[Mg]Cl
Agent: C=C[Mg]Cl
Agent: CC(C)CCCC(C)CCCC(C)CCl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 38 %

Procedure:
6.26 g (20 millimoles) of (2RS)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were dissolved in 20 ml of absolute THF. 16.2 ml of a 1.5-molar solution of vinyl-magnesium chloride in THF were added to the above solution at -20° C. and the mixture was stirred for 1 hour at the same temperature. Thereafter, a solution of (2RS,6RS)-1-chloro-2,6,10-trimethylundecyl-magnesium chloride, which had been prepared by reacting a solution of 0.86 g (35.8 millimoles) of magnesium in 10 ml of absolute THF with a solution of 8.16 g (34 millimoles) of (2RS,6RS)-1-chloro-2,6,10-trimethyl-undecane in 10 ml of THF and stirring the mixture for 2 hours at +70° C. was added dropwise to the above solution at -20° C., followed by dropwise addition of 1.4 ml of an 0.5-molar solution of di-lithium tetrachlorocuprate in absolute THF. The reaction mixture was then stirred for 3 hours at -20° C. and 15 hours at room temperature. After it had been worked up by the method of Example 1c, 3.3 g of α-tocopherol were isolated by distillation at 210° C./0.2 mbar. This corresponds to a yield of 38% of theory.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].C(C1C=C(C=CC=1)OCC([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)=O)=O>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[O:11])=[CH:12][CH:13]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Yield: 74 %

Procedure:
2-(4-Formylphenoxy)acetic acid (53) was treated in an analogous manner to Compound 49 to afford the desired product (74%) as a white solid. NMR: δ 1.461 (s, 9H), 3.38-3.64 (m, 8H), 4.802 (s, 2H), 2.06 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 9.899 (s, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:35]O>>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:35])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC(=O)O)c2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine (85 mg, 0.2 mmol, prepared in analogy to the one in Example 14-2) in methanol (10 mL) at 0° C. was added thionyl chloride (1.5 mL) carefully. The mixture was stirred at room temperature for 20 minutes, and then refluxed at 80° C. for 2 hours. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried over sodium sulfate, and concentrated in vacuo to afford the crude product which was directly used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20].[CH:24]1([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH:21]1([C:19]([N:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH:24]5[CH2:26][CH2:25]5)[CH:31]=4)[CH:3]=3)[NH:8][C@@H:7]([CH3:18])[CH2:6]2)=[O:20])[CH2:22][CH2:23]1
Reactant: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
A mixture of (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.100 g, 0.256 mmol), 1- cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.066 g, 0.281 mmol), chloro(2-dicyclohexyl phosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos Precatalyst 2nd Generation) (10.06 mg, 0.013 mmol), and cesium carbonate (0.250 g, 0.767 mmol) in dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 16 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100% ethyl acetate-hexane) to afford (S)-cyclopropyl(7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)methanone (0.065 g, 79%) as a yellow solid. MS (ESI, pos. ion) m/z 323 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-4 (2.00 g, 3.90 mmol) in MeOH (50 mL) was added an aqueous NaOH solution (10%, 10 mL). The resulting mixture was stirred at room temperature for 24 h, then was diluted with water (100 mL). The resulting mixture was adjusted to pH 4 using an aqueous HCl solution (2 N). The resulting crystals were collected, washed with water, and dried at 40° C. to give 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid (1.50 g, 79%) which was used without further purification:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][NH:7][CH2:6][C:5]2[CH:9]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:11][C:4]=2[S:3]1(=[O:17])=[O:16].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20].C(N(CC)CC)C.O>CN(C)C=O>[CH3:1][CH:2]1[CH2:8][N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:5]2[CH:9]=[C:10]([S:12](=[O:14])(=[O:15])[NH2:13])[S:11][C:4]=2[S:3]1(=[O:17])=[O:16]
Reactant: CC(C)CBr
Reactant: CC1CNCc2cc(S(N)(=O)=O)sc2S1(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN1Cc2cc(S(N)(=O)=O)sc2S(=O)(=O)C(C)C1
Temperature: 80 °C
Yield: 63.8 %

Procedure:
A solution of 2(R,S)-methyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepin-1,1-dioxide (1.18 g, 4.0 mmol) in dry dimethylformamide (6 mL) containing isobutylbromide (1.3 mL, 12 mmol) and triethylamine (2.3 mL, 16 mmol) was warmed at 80° C. for 20 hours in a sealed tube. The reaction mixture was poured into water and the product extracted into ethyl acetate. This extract was dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica gel and eluted with a 0-1% methanol/chloroform gradient to give 900 mg (64%) of title compound which slowly crystallized. Recrystallization from methylene chloride/butyl chloride gave analytically pure material, mp 158°-159.5° C.