Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.CN(OC)[C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.Cl>C1COCC1.CCOCC>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][C:9]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(CC(=O)N(C)OC)cc1OC
Reactant: [Li]c1cccs1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2cccs2)cc1OC
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
2-Lithiothiophene (1.0 M in THF, 33.0 mL, 33.0 mmol, Aldrich Chemical Co.) was added dropwise to N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide (5.26 g, 22.0 mmol) in anhydrous THF at -78° C. The reaction was allowed to proceed 90 min., then diluted with 100 mL Et2O and poured into 1 N aq. HCl. The aqueous phase was extracted with Et2O and the combined organic fraction was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography (25% EtOAc/hexanes) yielded 2.91 g (50%) 2-(3,4-dimethoxyphenyl)-1-(thien-2-yl)ethanone as a brown oil. MS 263 (M+H)+, 280 (M+NH4)+.
Reaction SMILES: Cl.[CH2:2]([C:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:10]2[C:9](=[O:11])[C:8]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:7]=[C:6]2[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:19][CH:18]=1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(Br)cc1

Procedure:
In this application further describes another process comprising the steps of reacting 2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one monohydrochloride (A) with 4-bromobenzyl bromide (B) in presence of base and solvent to give 3-[4-bromobenzyl]-2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one (C) which is condensed with 2-[2′-(triphenylmethyl-2′H-tetrazol-5′-yl)phenyl boronic acid in the presence of tetrakis triphenyl phosphine palladium and base to give Irbesartan (I).
Reaction SMILES: [CH3:1][CH:2]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H-].[Na+].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35]([NH:19][S:16]([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:1])(=[O:18])=[O:17])=[O:36])[CH3:23]
Reactant: CCCCCCCCCCCCCC(C)S(N)(=O)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(C)S(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
n-BuLi (1.6M, 32 mL) was added dropwise to a 0° C. solution of N-t-butylethanesulfonamide (4.0 g, 24 mmoles) in anhydrous THF (80 mL) under dry N2. The solution was stirred for 30 minutes at 0° C. then warmed to room temperature for 30 minutes. It was then cooled back to 0° C. and a solution of 1-bromotridecane (6.4 mL, 25 mmoles) in 10 mL anhydrous THF (distilled from Na--Ph2CO) was added dropwise. The solution was allowed to warm to room temperature overnight, quenched by addition of 1N HCl (60 mL), and partitioned between ethyl acetate and brine. The organic layer was dried, filtered, and concentrated to an oil, which was dissolved in 40 mL of CF3CO2H and stirred overnight at room temperature. It was then concentrated and the solid residue recrystallized from iPr2O to afford 4.8 g (68%) of 2-pentadecylsulfonamide as a light brown (almond) powder. (b) A solution of 2-pentadecylsulfonamide (2.91 g, 10 mmoles) in DMF (40 mL dried over 3Å sieves) was added dropwise to a stirred, 0° C. suspension of NaH (0.5 g, 21 mmoles of hexane washed) in 10 mL dry DMF. The mixture was stirred 30 minutes at 0° C., then warmed to room temperature for 3 hours. It was then cooled back to 0° C. and a solution of 2,6-diisopropylphenylisocyanate (2.14 mL, 10 mmoles) in 10 mL DMF was added dropwise. The mixture was allowed to warm to room temperature overnight, cooled to 0° C., and quenched by dropwise addition of 1N HCl (60 mL). The mixture was partitioned between EtOAc (300 mL) and H2O (100 mL). The organic layer was further washed with brine, dried, filtered, and evaporated to provide an oil which was flash chromatographed (silica gel, 4:1 hexane-EtOAc) to produce 3 g of an oil which solidified on standing (m.p. 65-75° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:3][CH:2]=1.Cl[CH2:25][S:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:30]1[CH:31]=[CH:32][C:27]([S:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[O:23])=[CH:28][CH:29]=1
Reactant: ClCSc1ccncc1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=c1c2ccccc2n(CSc2ccncc2)c(=O)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of 491 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione and 287 mg (1.8 mmol) of 4-chloromethylthiopyridine in 15 ml of dimethylformamide, 0.27 ml (1.8 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane=2:1 to 4:1 to ethyl acetate) to give 0.315 g of the desired product (46.7% yield, colorless oil).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:24]=[N:25][N:26]=3)[C:17]([C:20](OC)=[O:21])=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[OH:21][CH2:20][C:17]1[N:16]2[CH:24]=[N:25][N:26]=[C:15]2[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[N:19][CH:18]=1
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nncn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(CO)n3cnnc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A 250 mL 3-necked round bottom flask was charged with methyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine-5-carboxylate (3.0 g, 8.3 mmol) and dry CH2Cl2 (30 mL). To the above was added dropwise a solution of 1.5 M diisobutylaluminum hydride in toluene (11 mL, 16.5 mmol) at −78° C. The resulting mixture was stirred at −78° C. for further 1 h then quenched by slow addition of methanol (10 mL). The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with ethyl ether (100 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 3% MeOH in CH2Cl2, to afford 1.4 g (50%) of the product as a white solid. MS m/z: 335 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62]C1C=CC=CC=1C(O)=O)#[N:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62][C:29]1[CH:30]=[CH:31][CH:2]=[CH:3][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])#[N:55]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: N#Cc1ccccc1Sc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Sc3ccccc3C#N)nn2)cc(OC)c1OC
Yield: 80 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 2-[(2-cyanophenyl)thio]benzoic acid (217 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 2-[(2-cyanophenyl)thio]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (282 mg, 80%) as a yellow solid. MS m/z 542 (M+1).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:25])[CH2:23][CH3:24])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([CH2:26][N:27]([C:28]1[CH:29]=[CH:30][C:31]([Br:34])=[CH:32][CH:33]=1)[C:11]([C@@H:9]1[CH2:10][C@H:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)=[O:13])[C@@H:22]([CH3:25])[CH2:23][CH3:24])([CH3:16])([CH3:17])[CH3:15]
Reactant: O=C(O)[C@@H]1C[C@H]1c1cccc(F)n1
Reactant: CC[C@H](C)[C@@H](CNc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid (120 mg, 0.55 mmol) in thionyl chloride (2 mL) was heated at reflux for over night. The mixture was concentrated and dried under high vacuum for 3 h. Then the residue was dissolved in DCM (3 mL) and added dropwise to a solution of {(1S,2S)1-[(4-Bromo-phenylamino)-methyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (205 mg, 0.55 mmol) and triethyl amine (153 uL, 1.1 mmol) in DCM (3 mL). The resulting mixture was stirred at rt for overnight. The reaction mixture was concentrated and the residue was subjected to ISCO (12 g column, 0-40% EtOAc in hexane over 25 min.) to give the desired product (235 mg, 80%). MS (MH+ 534 and 536).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2=O)C1(C)C
Temperature: 65 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (prepared as described in Example 3, Step 1) (1 eq.), K2CO3 (2 eq.), methyl bromoacetate (2 eq.) in DMF was heated for 24 hours at 65° C. and then was cooled to room temperature. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the desired ester as a brown oil. MS (ES) C27H29FN4O5 requires 508. Found: 509 (M+H+).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (0.5 g, 0.0015 mol—Preparation 3), 5-formyl-2-furanylboronic acid (0.21 g, 0.0015 mol), sodium carbonate (0.32 g, 0.003 mol), toluene (20 mL), ethanol (10 mL) and water (5 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.053 g, 0.000075 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in n-hexane) to yield the desired product (0.38 g, 72%). 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 4.50 (br s, 4H), 3.91-3.88 (m, 4H): LC-MS (ESI): Calculated mass: 344.0; Observed mass [M+H]+: 345.0 (RT=1.39 min).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Cl[C:23]1[CH:31]=[CH:30][C:29]2[N:28]([CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH3:34])[C:27]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45][C:26]=3[C:25]=2[CH:24]=1.CC(C)([O-])C.[Na+].[CH2:53]([NH2:57])[CH2:54][CH2:55][CH3:56]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:53]([NH:57][C:23]1[CH:31]=[CH:30][C:29]2[N:28](/[CH:32]=[C:33](/[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)\[CH3:34])[C:27]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45][C:26]=3[C:25]=2[CH:24]=1)[CH2:54][CH2:55][CH3:56]
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Reactant: CCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: CCCCNc1ccc2c(c1)c1c(n2/C=C(\C)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
Palladium (II)acetate (314 mg, 1.4 mmol) and 2-(di-t-butylphosphino)biphenyl (418 mg, 1.4 mmol) were charged in a reaction bottle which was evacuated and backfilled with nitrogen. Toluene (10 mL) was added dropwise under nitrogen and stirred at RT overnight. The reaction mixture was passed through basic alumina using 0-30% ether:hexane and triturated with pentane to get brownish solid. Yield: 300 mg. 8-Chloro-5-(2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (50 mg, 0.282 mmol), Sodium tert-butoxide (81.2 mg, 0.846 mmol), and palladacycle [palladium (II)acetate+2-(di-t-butylphosphino)biphenyl) (10.7 mg, 0.0282 mmol)] were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (1 mL) was added under nitrogen atmosphere. Finally, butylamine (14.43 mg, 0.197 mmol) was added and the contents heated at 100° C. overnight. The reaction mixture was filtered and the precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 15 mg of free base. 1H NMR (CD3OD, free base) δ (ppm): 7.60 (m, 2H), 7.12 (t, 2H), 6.96 (d, 1H), 6.90 (s, 1H), 6.72 (s, 1H), 6.68 (d, 1H), 3.76 (s, 2H), 3.10 (t, 2H), 2.95 (m, 2H), 2.84 (m, 2H), 2.60 (s, 3H), 1.96 (s, 3H), 1.82 (q, 2H), 1.45 (q, 2H), 0.95 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](Cl)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:17][NH2:18])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(NN)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2,6-dichloroisonicotinate (11.0 g, 44.3 mmol) in ethanol (222 mL) was added hydrazine hydrate (6.46 mL, 133 mmol). The mixture was heated 75° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was concentrate down to half of the volume. The solid crashed out was filtered off and the filtrate was concentrated to dryness: LC-MS [M+1]=244.1.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH:13]2[CH2:17][O:16]C(C)(C)[O:14]2)=[O:10])=[CH:5][CH:4]=1.B(O)(O)O>COCCOCCOC.O>[CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH2:12][CH:13]([OH:14])[CH2:17][OH:16])=[O:10])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C(=O)OCC2COC(C)(C)O2)cc1
Agent: OB(O)O
Solvent: COCCOCCOC
Solvent: O
Product: CN(C)c1ccc(C(=O)OCC(O)CO)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
4-(4-Dimethylaminophenylcarbonyloxymethyl)-2,2-dimethyl-1,3-dioxolane from Example 4 (3 mmol) is dissolved in the diglyme/H2O 8:2 mixture (25 ml), and boric acid (2 g) is added. The reaction mixture is stirred at 100° C. for 3 h. The solvent is then distilled off in vacuo, the crude product which remains is taken up in water (100 ml) and extracted with ethyl acetate (3×20 ml). The combined organic phases are washed with water (2×50 ml) and dried over magnesium sulfate. The crude product remaining after evaporation of the ethyl acetate in vacuo is employed without further purification for subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][N:29]=[N:28]1)[C:10]([F:25])([F:24])[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][O:20][CH:21]([CH3:23])[CH3:22])=[CH:13][N:12]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][N:29]=[N:28]1)[C:10]([F:25])([F:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][CH:21]([CH3:23])[CH3:22])=[CH:13][N:12]=1
Reactant: CC(C)OC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)OCCCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-isopropoxyprop-1-en-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (54; 24 mg, 0.05 mmol) in CH3OH (2 mL) was added 10% Pd/C (2 mg), and the mixture was stirred under hydrogen atmosphere for 2 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of Celite®, and the Celite® cake was washed thoroughly with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 30% EtOAc/hexane) afforded 55 (20 mg, 0.04 mmol, 80%) as a colorless semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.36 (s, 1H), 7.89 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.36-7.31 (m, 1H), 6.77-6.73 (m, 1H), 6.67-6.63 (m, 1H), 5.56 (d, J=14.0 Hz, 1H), 5.09 (d, J=14.0 Hz, 1H), 3.53 (q, J=6.0 Hz, 1H), 3.38 (t, J=6.0 Hz, 2H), 2.75 (t, J=8.0 Hz, 2H), 1.86 (q, J=6.0 Hz, 2H), 1.14 (d, J=6.0 Hz, 6H). MS (ESI): m/z 454 (M+H)+. HPLC: 93%.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=2[NH:4][CH:3]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=2[N:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: Fc1cncc2c(Br)c[nH]c12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)n1cc(Br)c2cncc(F)c21
Yield: 56 %

Procedure:
Prepared according to the method described for Preparation 45 using 3-bromo-7-fluoro-1H-pyrrolo[3,2-c]pyridine (Preparation 48), 2-iodopropane and potassium carbonate as base. Purified using silica gel column chromatography eluting with 100% heptanes to 50:50 Heptane:EtOAc to afford the title compound (845 mg, 56%).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C([O-])(=[O:19])C.[K+].[OH-].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:16][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2][OH:19]
Reactant: CC(=O)[O-]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCCC(C)CCO
Yield: 94 %

Procedure:
For the verification of the optical purity the compound obtained is hydrogenated on pre-hydrogenated platinum dioxide to (3R,7R)-1-chloro-3,7,11-trimethyldodecane; boiling point at 0.07 mm; 90°; = -1.2° (4.08% in CHCl3), which is converted by heating with dry potassium acetate in dimethylformamide (4 hours at 170°). This ester is purified by adsorption on silicagel (elution agent: n-hexane/ether 4+1), then further reacted to (3R,7R)-3,7,11-trimethyl-1-dodecanol by stirring with 4-N aqurous caustic potash (30 min. at room temperature). The mixture is extracted, washed neutral, dried, concentrated, distilled in the bulb-tube (115°, 0.20 Torr) and there is obtained 3R,7R)-3,7,11-trimethyl-1-dodecanol in 94% yield (based on (3R,7R)-1-chloro-3,7,11-trimethyl-dodecane employed). The product has an optical rotation value of [α]D20 = +3.7° (4.14% in n-octane) and is accordingly identical with authentic material.
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].[C:18](=[O:28])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:19].CC(C)([O-])C.[Li+].O1CCCC1.O>O1CCCC1.C(OCC)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[CH:8][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([NH:19][C:18](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
80.0 mg (0.33 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6and 74.8 mg (0.50 mmol) of benzyl carbamate were dissolved in tetrahydrofuran (3 mL) and further mixed with a lithium tert-butoxide/tetrahydrofuran solution (1 mol/L, 0.50 mL, 0.50 mmol) at room temperature. After stirring at the same temperature for 1.5 hours, water (5.0 mL) was further added to the reaction solution and extraction with ethyl acetate (5 mL) was repeated three times. The residue obtained by concentrating the separated organic layer dried with anhydrous magnesium sulfate was purified on silica gel column chromatography to obtain benzyl (R)-{3-[4-(trifluoromethyl)phenylamino]-pentanoyl}carbamate as a white solid (112 mg, isolated yield: 86%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.98 (3H, t), 1.5-1.8 (2H, m), 2.9-3.2 (2H, m), 3.8-3.9 (1H, m), 4.2-4.3 (1H, br), 5.17 (2H, s), 6.60 (2H, d), 7.3-7.4 (7H, m), 7.5-7.6 (1H, br)