Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]([CH2:32][CH3:33])[CH:4]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]=[C:15]([NH:17][C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[O:19])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:34])[CH:3]([CH2:32][CH3:33])[CH:4]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]=[C:15]([NH:17][C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:19])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate (15 mg, 0.031 mmol) and lithium hydroxide (6.6 mg, 0.157 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 50° C. for 4 h. The reaction was evaporated, water was added and neutralized to pH 7. The slurry obtained was evaporated and extracted with DCM-methanol mixture and evaporated. The crude acid was purified by PTLC using DCM-methanol mixture as eluent to afford 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoic acid. MS ESI: m/462.11 [M−1−].
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][C:10]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=1)([CH3:18])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].O>C(COC)OC>[CH3:18][C:10]([C:19]1[S:20][C:21]([N+:7]([O-:8])=[O:6])=[C:22]([CH3:24])[CH:23]=1)([CH3:9])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: Cc1csc(C(C)(C)C(=O)N2CCCC2)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1[N+](=O)[O-]

Procedure:
Nitronium tetrafluoroborate (0.168 g, 1.26 mmol) was added to a solution of 1-[2-methyl-2-(4-methyl-2-thienyl)propanoyl]pyrrolidine (0.145 g, 0.61 mmol) in dimethoxy ethane (5 ml) cooled to −50 C. The mixture was allowed to warm to −30 C over 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and washed sequentially with a saturated solution of sodium bicarbonate and then with a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated to afford 1-[2-methyl-2-(4-methyl-5-nitro-2-thienyl)propanoyl]pyrrolidine as a yellow solid which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[C:24]([N:32]=[C:33]=[S:34])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:24]([NH:32][C:33]([NH:1][C:2]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1)=[S:34])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC1(c2cccs2)CN(C(=O)OCc2ccccc2)CC1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2cccs2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of benzyl 3-amino-4-(hydroxymethyl)-3-(2-thienyl)pyrrolidine-1-carboxylate (21 g, 63 mmol) in tetrahydrofuran (210 mL) at 0° C. is treated with benzoyl isothiocyanate (8.95 mL, 66.3 mmol. The resulting solution is stirred for 2 hours at 0° C. and quenched by adding an aqueous solution of sodium chloride and methyl-t-butyl ether. The organic layer is separated, dried over magnesium sulfate, and the solvent evaporated to give the title compound (30 g, 95%). ES/MS (m/e): 496 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:18][CH:17]([C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]4[CH:33]=[CH:34][N:35]=[C:29]4[CH:28]=3)=[O:24])=[CH:21][CH:20]=2)[CH2:16]1.[H-].[Na+].[CH3:40][CH:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>O1CCCC1>[N:35]1[CH:34]=[CH:33][N:30]2[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([CH:17]4[CH2:18][N:15]([S:43]([CH:41]([CH3:42])[CH3:40])(=[O:45])=[O:44])[CH2:16]4)=[CH:37][CH:36]=3)=[CH:28][C:29]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)N1CC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1
Reaction time: 1 h

Procedure:
In a 4 mL vial was mixed 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide bis(2,2,2-trifluoroacetate) (60 mg, 0.112 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature. To this mixture was added in portions 60% sodium hydride in mineral oil (22.45 mg, 0.561 mmol). This heterogeneous mixture was stirred 1 hour. To this was added propane-2-sulfonyl chloride (0.015 mL, 0.135 mmol) at and reaction mixture was stirred for 3 hours. The mixture was quenched with water, and product was extracted with 10% methanol/dichloromethane. The organic layers were combined, concentrated and purified by normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (m, 1H), 8.47 (d, J=7.0 Hz, 1H), 7.90 (m, 3H), 7.48 (m, 3H), 7.37 (s, 1H), 6.84 (m, 1H), 4.50 (d, J=5.9 Hz, 2H), 4.22 (m, 2H), 3.93 (m, 3H), 3.48 (m, 1H), 1.25 (d, J=5.9 Hz, 6H); MS (ESI(+)) m/e 413 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])=[CH2:3].[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=O>[O-2].[Zn+2]>[CH3:3][C:2](=[CH:4][CH:5]=[CH:6][C:7](=[O:9])[CH2:8][CH2:13][CH2:12][C:11]([CH3:15])=[CH2:10])[CH3:1]
Reactant: CC(C)=CC=O
Reactant: C=C(C)CCCC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: C=C(C)CCCC(=O)C=CC=C(C)C
Yield: 91 %

Procedure:
120 Parts of 2-methyl-1-hepten-6-one, 40 parts of 3,3-dimethyl-acrolein and 10 parts of zinc oxide are heated for 5 hours at 180° C and a pressure of 60 atmospheres. 63.5 Parts of 2,10-dimethyl-2,4,10-undecatrien-6-one having a boiling point of 120° to 123° C at 0.1 mm is obtained analogously to Example 9. The yield is 91% of theory (based on 3,3-dimethyl-acrolein) at a conversion of 78% of theory.
Reaction SMILES: [N:1]1([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1>[N:1]1([CH:6]=[C:7]([C:22](=[O:23])[C:21]2[CH:25]=[C:26]([F:30])[C:27]([Cl:29])=[CH:28][C:20]=2[Cl:19])[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C=CN1CCCC1
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCCC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 56.7 %

Procedure:
First a solution of 15.5 g of methyl 3-(1-pyrrolidinyl)acrylate in 25 ml of dioxane is added dropwise, and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 1 hour, heated to boiling under reflux for 30 minutes, and the solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/H2O. The phases are separated and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. The crystalline residue is recrystallized from cyclohexane. 19.6 g of methyl 3-(1-pyrrolidinyl)-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 74°-76° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13]>>[Cl:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([C:15]#[C:14][C:12]([CH3:13])([OH:16])[CH3:11])=[C:7]([F:8])[CH:6]=1
Reactant: Cc1cc(Br)c(F)cc1Cl
Reactant: C#CC(C)(C)O
Product: Cc1cc(C#CC(C)(C)O)c(F)cc1Cl

Procedure:
By the method of Example (IV-1), 100 mmol of 3-bromo-6-chloro-4-fluoro-toluene are reacted with 2-methyl-3-butin-2-ol to give 1-(4-chloro-2-fluoro-5-methyl-phenyl) -3-methyl-1-butin-3-ol, except that the mixture is only filtered after the reaction and not concentrated. The filtrate is then admixed with 1.5 g of sodium hydroxide (powder) and the mixture is heated to the boil in a distillation apparatus (with Vigreux column). Distillate is continuously removed, until the boiling point of triethylamine (89° C.) is reached. The mixture is then allowed to cool, filtered and washed with some ml of triethylamine. The filtrate is subsequently subjected to fractional distillation.
Reaction SMILES: [CH2:1]([C@:3]1([OH:19])[C:15]2[CH:14]=[C:13]3[N:9]([CH2:10][CH2:11][C:12]3=O)[C:8](=[O:17])[C:7]=2[CH2:6][O:5][C:4]1=[O:18])[CH3:2].[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][CH:30]=2)[C:25]1=O)(=[O:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:20]([NH:23][CH:24]1[C:25]2=[C:11]3[CH2:10][N:9]4[C:13](=[CH:14][C:15]5[C@:3]([CH2:1][CH3:2])([OH:19])[C:4](=[O:18])[O:5][CH2:6][C:7]=5[C:8]4=[O:17])[C:12]3=[N:34][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:26]=32)[CH2:32][CH2:33]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC1CCc2cccc(N)c2C1=O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2C(NC(C)=O)CC3
Reaction time: 24 h

Procedure:
361 mg of (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano-[3,4-f]indolizine-3,6,10(4H)-trione (hereinafter abbreviated as "trione") was added to the solution of 300 mg of the compound prepared in (4) above in 200 ml of toluene. The mixture was heated under reflux using a Deanstark apparatus for 10 minutes. To the mixture was added 1 mg of pyridinium-p-toluenesulfonate (hereinafter abbreviated as "PPTS") and the mixture was refluxed while stirring for a further 24 hours. After cooling, the residue obtained by removing toluene by concentration was suspended into 300 ml of chloroform-methanol (10:1) solvent. Insoluble substances were removed and the residue was powdered with methanol to obtain 336 mg of the title compound. mp: above 240° C. (decomposed)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[N:17]1([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.CCCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(CN2CCCC2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 106.2 %

Procedure:
To a solution of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, (0.15 g, 0.53 mmol) in N,N′-dimethylformamide is added 4-(pyrrolidinyl-methyl)aniline (0.10 mL, 0.58 mmol). The reaction mixture is heated at 120° C. under N2. Reaction is monitored by mass spectroscopy. After reaction is completed after 1.5 h. After evaporating the solvent, warm ethyl acetate is added to the residue to generate reddish orange residue. It is filtered through a pad of celite to give a yellow solution, which upon addition of hexane generated 0.24 g (62.8% yield) of orange solid: mp 165-166° C., Analysis for C21H20BrN3O2, Calcd: C, 59.17; H, 4.73; N, 9.86. Found: C, 58.77; H, 4.42; N, 9.81.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-].[C:18]([CH2:21][CH2:22][CH2:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:20])=[O:19].[H-].[Na+].CC(O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=[CH:24][CH2:23][CH2:22][CH2:21][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C1CCC(=CCCCC(=O)O)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
5 g (21.99 mmol) Methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester and 12.68 g (28.59 mmol) (4-Carboxy-butyl)-triphenyl-phosphonium bromide were dispended in 50 ml DMF. In small portions 2.49 g (57.2 mmol, 55%) NaH were added and the slurry was diluted by adding 50 ml DMF. The mixture was stirred at RT over night, 10 ml AcOH were added and the solvent was evaporated under reduced pressure. The residue was dissolved in ether and water, and the inorganic layer was extracted with ether. The combined organic phases were dried over and the crude materil was purified by column chromatography with ETOAc/hexane to give 5.86 g (83%) 5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexylidene]-pentanoic acid.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10]>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]([C:8]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([C:13]([O:15][CH3:16])=[O:14])[CH3:7])=[O:10]
Reactant: O=C1C=CCC1
Reactant: COC(=O)C(C)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C(=O)OC)C1CCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 133 μL (1.0 mmol) of dimethyl methylmalonate, and 1 mL of toluene were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 116 mg (51% yield) of the title compound. The optical rotation [α]D25 was +87.2(c 1.00, CHCl3). The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.5 mL/min, detection at 210 nm) and it was found to be 97% ee.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]=[C:9]([N:11]([CH3:20])[N:12]=CC1C=CC=CC=1)[S-])=O)(=O)C.[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=2)[O:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:24][CH2:23]1>>[CH3:20][N:11]1[C:9]([NH:36][CH2:35][CH2:34][CH2:33][O:32][C:31]2[CH:37]=[CH:38][CH:39]=[C:29]([CH2:28][N:25]3[CH2:24][CH2:23][CH:22]([OH:21])[CH2:27][CH2:26]3)[CH:30]=2)=[N:8][C:6]([CH2:5][OH:4])=[N:12]1
Reactant: NCCCOc1cccc(CN2CCC(O)CC2)c1
Reactant: CC(=O)OCC(=O)N=C([S-])N(C)N=Cc1ccccc1
Product: Cn1nc(CO)nc1NCCCOc1cccc(CN2CCC(O)CC2)c1
Yield: 32.5 %

Procedure:
Following the method of Example 17, N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate (0.75 g) and 3-[3-[1-(4-hydroxypiperidinyl)methyl]phenoxy]propanamine (0.65 g) gave 1-methyl-5-[[3-[3-[1-(4-hydroxypiperidinyl)methyl]phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (0.3 g), t.l.c. System B Rf 0.4. N.m.r. (CDCl3) 2.80,t,(1H); 3.0-3.3,m,(3H); 4.63,t,(1H); 5.52,s,(2H); 5.8-6.1,m,(5H); 6.3-6.7,m,(7H); 7.1-7.4,m,(2H) 7.7-8.7,m, (8H).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[N:18][N:19]=[C:14]2[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[N:18][N:19]=[C:14]2[C@H:13]([NH2:25])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 1 h
Yield: 122.2 %

Procedure:
Hydrochloric acid (4.0 M in dioxane; 10 mL, 40 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]carbamate (618 mg, 1.38 mmol) in 1,4-dioxane (5 mL). After 1 h, the reaction mixture was concentrated to give the bis hydrochloride salt of the title compound (584 mg). MS 347.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH3:10]I>>[CH3:10][N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CI
Product: Cn1cnc2c1CCNC2

Procedure:
Operating as in Example 1, but starting from 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine and methyl iodide, 1-Methyl-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine is obtained as intermediate and successively reacted with methyl isothiocyanate to give 1-Methyl-5-(N-methylthiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine in a 78% yield, m.p. 238° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a solution of 3-(tert-butyldimethylsilanyloxy)cyclopentanol (3.5 g, 16 mmol) in DCM (30 mL) was added triethylamine (2.65 mL, 19.4 mmol) and DMAP (20 mg, 0.16 mmol). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (1.34 mL, 16.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (20% diethyl ether:hexanes) afforded 2.5 g (53%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 5.19-5.3 (m, 1H), 4.4 (m, 1H), 3.0 (s, 3H), 1.8-2.3 (m, 4H), 1.5-1.7 (m, 2H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:26]([O:27][CH2:28][CH3:29])=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([OH:23])[CH:16]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:30][CH2:31][CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH2:31][CH3:32])=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:15]3[CH:16]=[C:17]([O:23][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:24])[CH2:9][CH2:8]2)=[CH:25][C:26]=1[O:27][CH2:28][CH3:29]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 72a), N-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 258) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 541.2 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na].C([BH3-])#N>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Reactant: O=CCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na]
Solvent: O
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and hydrocinnamaldehyde (0.94 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium i 15 cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The solvent was decanted and the semi-solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude compound was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to give the title compound (1.18 g, 94% yield) as a brown oil.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.S([O-])(=O)(=O)C.[I-:22].[Na+].C(=O)(O)[O-].[Na+]>CC(C)=O>[I:22][CH2:6][C:7]#[C:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCC#CCOc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: ICC#CCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
By following the esterification method of part B of this preparation, the preceding compound was converted into 4-phenoxybut-2-yn-1-ol methanesulfonate in almost quantitative yield. The foregoing crude mesylate was dissolved in 15 ml of acetone and treated with a solution of 5.55 g (0.037 mol) of sodium iodide and 1.049 g (0.0123 mol) of sodium bicarbonate in 30 ml of acetone. The reaction mixture was stirred for 1 hour at room temperature and then the solvent was removed under reduced pressure. The residue was diluted with water and extracted with methylene chloride; the organic extracts were dried and evaporated. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (95:5) as eluant, to yield 1-iodo-4-phenoxybut-2-yne.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:31]=4[CH:32]=[CH:33][C:24]([CH3:23])=[N:25]5)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc2c(B(O)O)cccc2n1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: Cc1ccc2c(-c3cc(-c4cnc5c(F)c(C(C)(C)O)ccn45)ccc3F)cccc2n1
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-methylquinoline-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methylquinolin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 430 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16](O)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16]([Cl:28])[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(O)c2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(Cl)c2CC1
Temperature: 25 °C

Procedure:
To a suspension of 3.0 g (8.86 mmol) 10-hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester in 6 mL toluene was added 7 mL (74.06 mmol) of phosphorus oxychloride and 1.28 mL (7.35 mmol) of DIPEA, and the reaction was heated at reflux for 40 minutes. The mixture was cooled to room temperature and poured into ice. The aqueous phase was extracted with DCM (3×20 mL) and the combined organic layers were dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 7:3).