Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H](CCCCCCCCCC(C)C)CC(O)=O)C1C=CC=CC=1.BrC1C=CC([C@:33](CC=O)([CH:37]([O:52][C:53](=[O:69])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[C:34]([O-:36])=[O:35])=CC=1>[Zn]>[C:53]([O:52][C@H:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]([CH3:50])[CH3:51])[CH2:33][C:34]([OH:36])=[O:35])(=[O:69])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)[C@](CC=O)(C(=O)[O-])c1ccc(Br)cc1
Agent: CC(C)CCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Agent: [Zn]
Product: CCCCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCCC(C)C)CC(=O)O
Yield: 95.8 %

Procedure:
In a manner similar to the synthesis of 107, compound 120 (500 mg, 0.666 mmol) was treated with zinc (<10 micron, 430 mg, 6.66 mmol) to afford 109 as an amorphous solid (335 mg, 96%). Rf=0.35 (toluene/ethyl acetate, 4/1, v/v); [0]25D=−0.6° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 5.19 (m, 1H, H-3), 2.58 (m, 2H, H-2), 2.25 (t, 2H, J=7.5 Hz, H-2′), 1.60-1.43 (m, 5H, H-4, H-15, H-3′), 1.23-1.14 [m, 44H, H-(5-14), H-(4′-15′)], 0.85-0.83 (m, 9H, H-16, H-16′); 13C NMR (75 MHz, CDCl3): δ 176.24 (C═O), 173.27 (C═O), 69.95 (C-3). HR MS (m/z) calculated for C33H64O4 [M Na]+, 547.4697; found, 547.5009.
Reaction SMILES: NC1SC2CC(N)CCC=2N=1.[Br:12]Br.[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)(=[O:16])[CH3:15]>O>[Br:12][CH:22]1[CH2:23][CH:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19][CH2:20][C:21]1=[O:24]
Reactant: BrBr
Reactant: CC(=O)NC1CCC(=O)CC1
Agent: Nc1nc2c(s1)CC(N)CC2
Solvent: O
Product: CC(=O)NC1CCC(=O)C(Br)C1

Procedure:
According to one aspect of the present invention there is provided a method of synthesising 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole, which method comprises comprising: (i) reacting bromine with a solution of 4-acetamido-cyclohexanone in water to produce 2-bromo-4-acetamido-cyclohexanone; (ii) after step (i), adding thiourea to produce 6-acetylamino-2-amino4,5,6,7-tetrahydro-benzthiazole-dihydrobromide; (iii) after step (ii), adding an aqueous solution of hydrobromic acid to produce 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole; and (iv) after step (iii), isolating 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole free base.
Reaction SMILES: C(=O)([O-])O.[Na+].Br[C:7]1[N:11](CC2C=CC(OC)=CC=2)[N:10]=[C:9]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:8]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.Br[C:34]1[C:38]([C:39]2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)N=1.C1(B(O)O)CC1>C(COC)OC.O.C(OCC)(=O)C>[Cl:26][C:23]1[S:22][C:21]([C:9]2[C:8]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[C:7]([CH:39]3[CH2:38][CH2:34]3)[NH:11][N:10]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Reactant: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Agent: O=C([O-])O
Agent: OB(O)C1CC1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Clc1ccc(-c2n[nH]c(C3CC3)c2-c2ccncc2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a mixture of sodium hydrogen carbonate (2.0 mmol) and PdCl2dppf:CH2Cl2 1:1 (0.05 eq, 0.03 mmol) under argon, was added a degassed solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 0.65 mmol) in 10.5 mL dimethoxyethane and 3 mL of water. Cyclopropylboronic acid (1.3 mmol) was then added and the mixture was stirred at 90° C. for 3 h. Further cyclopropylboronic acid was then added (1.3 mmol), and the mixture was stirred overnight at 65° C. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (Column WATERS Sunfire C18.5 μm 50*150 mm, eluent:water/methanol/0.1% formic acid) to afford 49 mg of 4-[3-(5-chloro-2-thienyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine (25% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:15]=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:15]=[N:16][CH:17]=1
Reactant: CC(C)(CO)c1cncc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride in dichloromethane (2.0 M, 0.869 mL, 1.74 mmol) was diluted with dichloromethane (2 mL) and then a solution of dimethylsulfoxide (0.250 mL, 3.50 mmol) in dichloromethane (1 mL) was added at −78° C. After stirring for 15 minutes, a solution of the title compound from Example 53 Step E (0.200 g, 0.869 mmol) in dichloromethane (3 mL) was added. The resulting reaction stirred for 30 minutes before triethylamine (0.600 mL, 4.35 mmol) was added. The reaction warmed to room temperature slowly and stirred overnight. It was quenched with the addition of water and then extracted with dichloromethane. The combined organics were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (25-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 229.87 [M+2H]+; 1H NMR (500 MHz, CDCl3) δ 9.53 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 7.73 (s, 1H), 1.51 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35](Cl)(=[O:37])=[O:36])[CH:33]=2)[NH:28][N:27]=1.C([O-])(O)=O.[Na+].CCCCCC>ClCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:35]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:25])(=[O:37])=[O:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1n[nH]c2ccc(S(=O)(=O)Cl)cc12
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(S(=O)(=O)N(CC(C)C)CC(O)C(Cc3ccccc3)NC(=O)OC(C)(C)C)cc12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester 15 (60 mg, 0.18 mmol) and 3-methyl-1H-indazole-5-sulfonyl chloride (50 mg, 0.22 mmol) in 2 mL dichloromethane was added a 70 ul solution of a saturated NaHCO3 and 30 mg NaHCO3 and stirred overnight. The product was purified by preparative TLC using 1:1 ethyl acetate: hexane to give 95 mg product (99% yield). MS 531 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[N:4][C:3]=1[O:14][CH3:15].[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>O1CCOCC1.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[CH3:15][O:14][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH:16]=[CH2:17])[N:9]([CH3:12])[C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: COc1nc2c(cc1Br)N(C)C(=O)CC2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc2c(nc1OC)CCC(=O)N2C
Temperature: 100 °C
Yield: 36.7 %

Procedure:
A mixture of 690 mg (2.5 mmol) of 7-bromo-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one, 0.8 ml (2.7 mmol) of tri-n-butyl-vinyltin and 100 mg of bis(triphenylphosphine-palladium(II) chloride in 20 ml of dioxane was heated under nitrogen to 100° C. for 6 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The ethyl acetate solution was washed with water several times. To this ethyl acetate solution was added 1 ml of saturated KF, and the mixture filtered. The filtrate was dried, evaporated, and the residue chromatographed on silica using 1 5 ethyl acetate/hexanes as the elutant. Appropriate fractions were combined and evaporated to afford 200 mg of 6-methoxy-1-methyl-7-vinyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. 1H NMR (CDCl3) δ 7.28 (s, 1H), 6.90 (d,d 1H), 5.75 (d, 1H), 5.35 (d, 1H), 3.95 (s, 3H), 3.26 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H) Mass spectrum: m/e=219.3 (p+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1C[O:31]CC1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2([OH:31])[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
n-Butyl lithium (16 mL, 2.5M solution in hexanes, 39.9 mmol) was added to a solution of 1-bromo-4-chlorobenzene (8.62 g, 45.0 mmol) in anhydrous THF (100 mL) at −78° C. under nitrogen. After 30 minutes at −78° C., 1-Boc-piperidone (6.62 g, 33.2 mmol) was added dropwise as a solution in anhydrous THF (5 mL). After 30 minutes at −78° C., the reaction was quenched with a saturated NH4Cl solution (100 mL), extracted with EtOAc (2×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane (0-40%) to give tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (7.64 g, 74% yield). 1H NMR (CDCl3, 400 MHz) δ 7.38 (d, J=7.2 Hz, 2H), 7.15 (d, J=7.3 Hz, 2H), 3.94 (br s, 2H), 3.18 (br s, 2H), 1.89 (br s, 2H), 1.46 (s, 11H). LCMS: M+1 312.2.
Reaction SMILES: C[N:2](C)/[C:3](/[CH3:26])=[CH:4]/[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:25])[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=O.O.[NH2:29]N.C(O)(=O)C>C(O)C>[CH3:26][C:3]1[NH:2][N:29]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:25])[CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:4]=1
Reactant: NN
Reactant: C/C(=C\C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12)N(C)C
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a solution of (E)-N-(2-(3-(dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (139 mg, 0.37 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate (1 mL, 62.91 mmol) and acetic acid (0.5 mL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under N2 (g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20:80 ethyl acetate/hexane) yielded N-(2-(5-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (20 mgs, 16%). Method [7] m/z 348.1 (M+Na); retention time=6.791. 1H-NMR (CDCl3) δ 10.28 (broad s, 1H), 8.07 (d, J=5.8 Hz, 2H), 7.91 (d, J=4.5 Hz, 2H), 7.53 (d, J=5.8 Hz, 2H), 7.53 (s, 1H), 7.50 (d, J=4.5 Hz, 2H), 7.08 (d, J=5.2 Hz, 1H), 5.88 (s, 1H), 4.23 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(=O)n1C
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 90 °C
Yield: 82.3 %

Procedure:
A mixture containing 0.2 g (0.84 mmol) of 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one, 0.19 g (1.3 mmol) of 2,4-dimethylphenyl boronic acid, 0.35 g (2.5 mmol) of potassium carbonate, 0.15 ml (8.4 mmol) of water, and 0.25 g (0.21 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 ml of dioxane was heated to 90° C. under a nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 30% ethyl acetate/hexanes gave 0.18 g (86%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].O.S(=O)(=O)(O)O.[I:26](O)(=O)=O>C(O)(=O)C.II>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([I:26])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 289.2 %

Procedure:
5.08 g of 4-methyl-β-carboline-3-carboxylic acid ethyl ester is dissolved in 40 ml of glacial acetic acid and combined with 0.96 ml of water, 0.24 ml of concentrated sulfuric acid, 688 mg of iodic acid, and 1.768 mg of iodine. The mixture is heated to 80° C. for 3 hours. After cooling, the mixture is suctioned off from undissolved material, and the filtrate is evaporated. The residue is taken up in ethanol/water. The thus-formed crystals are suctioned off, taken up in 500 ml of ethyl acetate, and extracted by stirring with 200 ml of 1N sodium hydroxide solution for 15 minutes. The organic phase is separated, concentrated by evaporation, the residue is extracted by stirring in ethyl acetate, and vacuum-filtered, thus obtaining 4.3 g of 6-iodo-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 250°-255° C.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH3:14].[CH3:15][O:16]C(Cl)Cl>ClCCl>[CH3:6][C:7]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=1[S:13][CH3:14])[CH:15]=[O:16]
Reactant: CSc1ccccc1C
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(C=O)cc1C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
Tin (IV) chloride (13.6 ml, 0.116 mol) was added to an ice-bath cooled solution of 1-methyl-2-(methylthio)benzene (10 g, 0.073 mol) in anhydrous dichloromethane (200 ml) under nitrogen and stirred for a further 2 hours at 0° C. α,α-Dichloromethyl methyl ether (6.56 ml, 0.073 mol) was introduced and the reaction stirred for 1 hour at <10° C. before the cooling was removed. After attaining room temperature, the reaction mixture was poured into ice/water (400 ml), stirred and then extracted with dichloromethane (×3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated onto silica gel and purified by flash chromatography, eluting with diethyl ether/isohexane (10:1) to yield the subtitle compound as a brown oil (6.54 g) in 54% yield.
Reaction SMILES: C([O:8][C@H:9]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][Cl:16])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]=O>[Cl:16][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH2:10][C@@H:9]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[OH:8])=[O:17]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OCc1ccccc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(=O)CCCCl

Procedure:
A solution of 0.4 g of (R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 20 ml of glacial acetic acid is treated with 0.120 g of palladium oxide and hydrogen. The catalyst is removed by filtration under suction and the filtrate is dried under reduced pressure. There is obtained (R)-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine of melting point 48° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN([CH:66]=[O:67])C.[CH3:68][CH2:69][OH:70]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:66]([O:70][CH2:69][CH3:68])=[O:67])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: CC(c1cnc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Reactant: CN(C)C=O
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nccc2c1CN(C(C)c1cnc(OCC(F)(F)F)c(Cl)c1)C2=O
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 4-chloro-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (200 mg, 0.49 mmol, Intermediate-9, single enantiomer), palladium(II) acetate (33 mg, 0.15 mmol, 1,3-bis(diphenylphosphino)propane (20 mg, 0.049 mmol), and triethylamine (150 mg, 1.5 mmol) in DMF/EtOH (2:1, 14 mL) is heated at 100° C. overnight under carbon monoxide atmosphere. The mixture is diluted with water, and filtered through a pad of Celite™. The Celite™ pad is washed with EtOAc/toluene (2:1) mixed solvent. The filtrate is washed with water, brine, and dried over sodium sulfate. The organic layer is filtered, and the filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1 to 1:2) to give 160 mg (73% yield) of the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=1[O:54][CH2:55]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:55][O:54][C:53]2[CH:58]=[CH:59][CH:60]=[CH:61][C:52]=2[F:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCOc1ccccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCOc4ccccc4F)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 71 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (55 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (76 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(2-fluorophenoxy)-1-ethanol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 66%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:22])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Temperature: 25 °C

Procedure:
A suspension of 15.07 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 10.10 g of potassium carbonate in 260 ml of acetone is admixed with 5.43 ml of dimethyl sulphate and stirred at reflux over 7 hours. The reaction mixture is cooled to room temperature and concentrated by evaporation. The residue is partitioned between diethyl ether and a 1:1 25% conc. ammonia-water mixture. The organic phase is washed with water, 2N NaOH (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a white solid from the residue. Rf=0.30 (1:1 EtOAc-heptane); Rt=4.22.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33](=[O:35])[NH2:34])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl>[CH:36]1([NH:39][CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:33]([NH2:34])=[O:35])=[C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:30])([F:31])[F:32])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Solvent: ClCCl
Product: NC(=O)c1sc(-n2cnc3cnc(CNC4CC4)cc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 6, 58 mg of [1-(5-carbamoyl-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (compound A1) and 228 mg of cyclopropylamine in 5 ml dichloromethane yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[Br:13][C:14]1[CH:15]=[C:16]2[CH:22]=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([C:10](=[O:11])[CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)Cc1cccc(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
2,3-Difluorophenylacetyl chloride(58.1 mmol) in CH2Cl2 (150 ml)was added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (8.0 g, 40.6 mmol) and AlCl3 (46 g, 345 mmol) in CH2Cl2 (100 ml) at 0° C. After the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hrs. The reaction was cooled with ice-bath and methanol (100 ml) was added to the reaction mixture while maintaining the temperature below 30° C. The reaction mixture was evaporated and the residue was suspended in water. The solid was collected by vacuum filtration, washed with water and hexane to give the title compound (14.03 g) in 98% yield.