Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[CH3:8]
Reactant: Cc1ncc(Br)cc1N
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1nc2ccc(-c3cnc(C)c(N)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.33 h
Yield: 50.1 %

Procedure:
5-bromo-2-methylpyridin-3-amine (224.9 mg, 1.202 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (413.7 mg, 1.300 mmol), potassium carbonate (549.4 mg, 3.975 mmol), and Pd(dppf)Cl2*DCM complex (108.7 mg, 0.133 mmol) were suspended in DME (5.0 ml) and water (1.25 ml), and the flask was fit with a reflux condensor and argon was bubbled through for about 15 seconds. Then, the flask was placed in a preheated oil bath (100° C.) and stirred under argon for 80 minutes. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated, treated with MeOH, and filtered. Solid washed with MeOH, water, MeOH, and Et2O. Solid then collected and dried under high vacuum to afford N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (179.7 mg, 50% yield). MS (ESI pos. ion) m/z: 299. Calculated exact mass for C15H14N4OS: 298.
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4].ClC(C(=O)CC)C(OC)=O.C(Cl)Cl.P>[Ru].CO>[Cl:1][CH:2]([C@H:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCCCCCCCCCC(=O)C(Cl)C(=O)OC
Agent: [Ru]
Agent: CCC(=O)C(Cl)C(=O)OC
Agent: P
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCC[C@@H](O)C(Cl)C(=O)OC
Yield: 95.3 %

Procedure:
In a 500 ml Hastelloy-made autoclave having been purged with nitrogen were put 100 g (0.2886 mol) of the methyl 2-chloro-3-oxooctadecanoate (VII) prepared in (1) above, 2 ml of a methylene chloride solution of 260 mg (0.144 mol) of a ruthenium-optically active phosphine complex Ru2Cl4 [(+)-Tol-BINAP]2NEt3, and 300 ml of methanol, and the mixture was allowed to react at 50° C. under a hydrogen pressure of 30 atm for 18 hours. Methanol was removed by evaporation to give 95.8 g (0.275 mol; yield: 95.3%) of the title compound (VIII) (melting point: 39-40° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21][C:20]=3[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21][C:20]=3[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoate (220 mg, 0.53 mmol) in DCM (5 mL) was added trifluoroactic acid (5 mL). After stirred at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was used in next step without further purification (0.22 g, crude). LCMS (ESI) m/z: 361.0 [M−H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([S:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C(Cl)[Cl:12]>>[Cl:12][CH2:2][C:3]1[CH:4]=[C:5]([S:9][CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(CO)c1
Reactant: ClCCl
Product: CSc1cccc(CCl)c1

Procedure:
3-Hydroxymethyl-1-methylthiobenzene (3.3 g, 21 mmol) is dissolved in absolute CH2Cl2 (20 ml) under an argon atmosphere. A solution of SOC12 (2.6 g, 21 mmol) in absolute CH2Cl2 (10 ml) is added dropwise with stirring to this initial mixture in the course of 15 min, initially under reflux, then at an internal temperature of 30° C. The reaction mixture is stirred under reflux for 2.25 h. The reaction mixture is concentrated and the oily crude product is purified by bulb tube distillation (7.9×10−2 mbar, 125-140° C.): colorless oil; yield: 3.3 g (88%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[NH3:18]>>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[N:18])=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C[C@H]1CCCN1[C@H]1C[C@H](c2ccc(Br)cc2)C1
Reactant: N
Product: C[C@H]1CCCN1[C@H]1C[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 1C except substituting the product from Example 13A for the product from Example 1B. 1H NMR (300 MHz, CD3OD) δ 1.36 (d, J=6 Hz, 3 H), 1.72 (m, 1 H), 2.01 (m, 2 H), 2.24 (m, 1 H), 2.55 (m, 1 H), 2.63 (m, 1 H), 2.78 (m, 2 H), 3.02 (m, 1 H), 3.25 (m, 1 H), 3.42 (m, 1 H), 3.69 (m, 1 H), 3.90 (m, 1 H), 7.47 (d, J=9 Hz, 2 H), 7.68 (d, J=9 Hz, 2 H), 7.80 (AB q, 4 H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:23]=[CH:22][N:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:23]=[CH:22][N:21]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Reactant: NNc1cc(N2CCCCC2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 323 mg (1.7 mmol) of the compound from Example 8A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 2 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@H:13]([F:27])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:28][C:29]1[C:38]([F:39])=C(F)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:28][C:29]1[C:38]([F:39])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@H:13]([F:27])[CH2:12]2)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@@H](F)[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 18 h
Yield: 42.7 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoropyrrolidine (400 mg, 1.06 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 500 mg) and stirred for 18 hours under a hydrogen atmosphere. The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (8 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (289 mg, 0.88 mmol) and triethylamine (2 ml) and stirred for 26 hours at 100° C. in a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (80 ml) and washed-with a 10% citric acid aqueous solution (80 ml) and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with a mixture of chloroform:methanol=9:1, and the eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 20 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml×2), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (200 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Thereafter, the resulting residue was purified by recrystallization from ethanol and then dried under reduced pressure to obtain 170 mg (42.6%) of the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[C:25]([Mg]Cl)#[CH:26]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[C:25]#[CH:26])=[CH:4][CH:3]=1
Reactant: C#C[Mg]Cl
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (100 mg, 0.263 mmol) in tetrahydrofuran (1.5 mL) was added dropwise ethynylmagnesium chloride (0.5 M solution in tetrahydrofuran, 1.05 mL, 0.525 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (99.3 mg, 0.244 mmol, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccccc1Br
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)ccc1Oc1ccccc1Br
Temperature: 120 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (0.203 g, 1 mmol) in DMA (2.5 mL) were added 2-bromophenol (0.182 g, 1.05 mmol) and potassium carbonate (0.138 g, 1 mmol), followed by stirring at 120° C. for 12 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue was purified through column chromatography (20% ethyl acetate/hexane) and concentrated to obtain the object compound (0.164 g, 46%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][Cl:21])[OH:19])[CH3:9].[C:22]([N:26]=[C:27]=[O:28])(=[O:25])[CH:23]=[CH2:24].O>ClCCl>[C:22]([NH:26][C:27]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][Cl:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:28])(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)N=C=O
Reactant: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NC(=O)OC1CCC(O)(CCl)C(C2(C)OC2CC=C(C)C)C1OC
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a solution of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (418 mg) in dichloromethane (5 ml) was added dropwise acryloylisocyanate (300 mg). The mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: hexane-ethyl acetate=4:1) to afford 4-O-(acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (200 mg, yield 38%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[N:10]=[C:4]2[CH:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20]>>[C:22]([O:21][C:19](=[O:26])[NH:20][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[N:10]=[C:4]2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(N)=O
Reactant: COc1ccccc1-c1nc2cc(Br)ccn2n1
Product: COc1ccccc1-c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Yield: 94.9 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (490 mg, 1.61 mmol) and tert-butyl carbamate (350 mg, 2.99 mmol) as starting materials. The reaction affords [2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (520 mg, 94.8%) as a light yellow solid. mp.: 202.8° C., MS: m/z=341.1 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:31]=4[NH:30][C:29](=[O:32])[CH2:28]5)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O>C(O)C.N1CCCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:31]=4[NH:30][C:29](=[O:32])[C:28]5=[CH:40][C:36]4[NH:35][CH:39]=[CH:38][CH:37]=4)[CH:17]=3)=[O:14])=[CH:33][CH:34]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5)c3)cc2)CC1
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5=Cc4ccc[nH]4)c3)cc2)CC1

Procedure:
A solution of 4-(4-methyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-phenyl]-benzamide (23 mg, 0.05 mmol) is heated with 1H-pyrrole-2-carbaldehyde (5 mg, 0.05 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine for 12 hours. It is then concentrated and purified by HPLC to give the desired compound: 1H NMR (DMSO-d6) δ 2.40-2.48 (m, 2H), 2.79 (s, 3H), 2.96-3.08 (m, 4H), 3.36-3.46 (m, 2H), 3.75 (s, 2H), 6.37 (s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.85 (s, 1H), 6.97 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.2 Hz), 7.19 (t, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.30 (t, 1H, J=7.8 Hz), 7.36 (s, 1H), 7.47 (d, 2H, J=7.8 Hz), 7.53 (s, 1H), 7.75 (s, 1H), 7.93 (d, 2H, J=7.8 Hz), 10.13 (s, 1H), 10.60 (s, 1H), 13.36 (s, 1H); LC-MS: 533.2 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C., where it was stirred for 25 min. The reaction mixture was then treated with 2-aminopyridine (91 mg, 0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide (106 mg, 58%) as a white foam: mp 92-95° C. (foam to gel); FAB-HRMS m/e calcd for C20H23N3O5S (M+H)+ 418.1436, found 418.1430.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(F)=C(F)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1ccc(CBr)cc1F
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(F)c(F)c3)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.07 g) using 3,4-difluorobenzyl bromide (0.4 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.22-7.20 (m, 1H), 7.07-7.02 (m, 1H), 6.96-6.92 (m, 1H), 5.26 (s, 2H), 3.06-3.02 (m, 4H), 2.94-2.91 (m, 2H), 2.87-2.84 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:16]#[N:17].[Na+]>O>[C:16]([CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:17]
Reactant: [C-]#N
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC#N)C2
Temperature: 80 °C
Yield: 102.4 %

Procedure:
2-Bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.5 g, 18.6 mmol) was dissolved in dimethylsufoxide (30 ml). Sodium cyanide (1.43 g, 88 mmol ) was added and the resulting mixture was stirred at 80° C. for hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 2:.i). The crude crystals obtained were recrystallized from methanol to obtain the desired compound (4.1 g, yield: 79.7%), m.p. 58°-59° C.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.C[Mg]Br.C(OCC)C.[CH2:17]([O:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:28][C@H:27]([O:39][CH3:40])[C:26]1=[O:41])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:28][C@H:27]([O:39][CH3:40])[C@:26]1([CH3:5])[OH:41])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1=O
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)O
Temperature: 0 °C

Procedure:
92 mL of a 1 mol/L methyl magnesium bromide/tetrahydrofuran solution and 23 mL of a 3 mol/L methyl magnesium bromide/diethyl ether solution were added dropwise to a solution of 23.2 g of (2S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxyoxolane-3-one in 100 mL of tetrahydrofuran at −40° C., and the obtained mixture was then stirred at the same temperature as described above for 30 minutes. Thereafter, the temperature of the reaction mixture was increased to 0° C. over 1 hour, and 500 mL of a saturated ammonium chloride aqueous solution and 500 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was washed with 300 mL of a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography, so as to obtain 12.0 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol in the form of a colorless oily product.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]1([N:24]2[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[CH:33](O)[CH3:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl>[N:15]([CH:33]([C:25]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1nc2ccncc2n1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2ccncc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 165.2 %

Procedure:
Diphenylphosphoryl azide (1.12 g, 4.06 mmol) and then diisopropyl azadicarboxylate (1.37 g, 6.77 mmol) were added to a stirred solution of 1-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)ethanol (0.81 g, 3.39 mmol) and triphenylphosphine (1.78 g, 6.77 mmol) in dioxane (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 20° C. for 16 h then diluted with DCM to dissolve all the material. This was loaded onto an Isolute® SCX-2 cartridge and washed with methanol and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography (SiO2 0-4% (2M ammonia in methanol) in DCM) to give the title compound as a colourless oil (1.48 g, contaminated with triphenylphosphine oxide). LCMS (method H): Rt 1.79 min, [M+H]+ 265.