Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:33](=[O:34])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19]Cl)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)COc4ccccc4)C(=O)N23)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=C1CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 97 %

Procedure:
To a solution of 48 ml of SmI2 in THF (0.1M), a solution of 1.1 g of p-methoxybenzyl 7β-phenoxyacetylamino-3-chloromethyl-3-cephem-4carboxylate in 100 ml of dry THF, was added by dropping at -78° C. The resulting mixture was allowed to warm to room temperature in 0.5 hours. Water was added, and the mixture stirred for further 0.2 hours at room temperature. After the usual work-up and column chromatography, the title produce was isolated in 97% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Cl[C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH2:50])=[O:49])=[CH:46][N:45]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[CH:52]=[CH:51][C:47]([C:48](=[O:49])[NH2:50])=[CH:46][N:45]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccc(C(N)=O)cn3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 6-chloronicotinamide.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[C:4][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2
Reactant: C#CC(C)(C)N
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC(C)(C)N)c21

Procedure:
Using Method C above, 3-amino-3-methyl-1-butyne (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 5 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-[3-amino-3-methyl-1-butynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 44 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(#N)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[N:13]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(=O)n(CCOc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)-(1H)-pyridin-2-one (1 eq, 0.30 mmol, 60 mg) in THF (3 mL) was added K2CO3 (10 eq, 3.00 mmol, 0.41 g). The reaction was stirred at room temperature for 30 minutes then 1-(2-bromoethoxy)benzene (3 eq, 0.90 mmol, 0.18 g) was added. The reaction was stirred at 60° C. for 12 hours. After concentration of the solvent, acetonitrile (3 mL) was added followed by K2CO3 (10 eq, 3.00 mmol, 0.41 g) and 1-(2-bromoethoxy)benzene (10 eq, 3.00 mmol, 0.60 g) then the reaction was microwaved for 5 minutes at 180° C. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt (80/20) as the eluent to afford 5-(4-methoxyphenyl)-1-(2-phenoxyethyl)pyridin-2(1H)-one (0.13 mmol, 42 mg, 44%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:15][NH:16][C:17]([C:19]1[N:20]([CH3:25])[N:21]=[CH:22][C:23]=1[NH2:24])=[O:18]>>[CH3:25][N:20]1[C:19]([C:17](=[O:18])[NH:16][CH3:15])=[C:23]([NH:24][C:12]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH:8]3[CH2:9][CH2:10][CH2:11]3)[N:4]=2)=[O:14])[CH:22]=[N:21]1
Reactant: O=C(O)c1nc(C2CCC2)ncc1Br
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(C3CCC3)ncc2Br)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-cyclobutyl-pyrimidine-4-carboxylic acid (37 mg, 0.14 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (29 mg, 0.19 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as off-white solid (24 mg, 42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2/[CH:18]=[C:19]1\[O:20][C:21]2[C:28]([CH2:29][N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)=[C:27]([OH:43])[CH:26]=[CH:25][C:22]=2[C:23]\1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>C(Cl)Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2/[CH:18]=[C:19]1\[O:20][C:21]2[C:28]([CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:27]([OH:43])[CH:26]=[CH:25][C:22]=2[C:23]\1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c(OCc5ccccc5)cccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3c(OCc4ccccc4)cccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[7-(benzyloxy)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.025 g, 0.043 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was washed with methylene chloride to obtain (Z)-2-{[7-(benzyloxy)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.017 g, 71%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:37]12[NH:44][CH:41]([CH2:42][CH2:43]1)[CH2:40][CH:39]([OH:45])[CH2:38]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:44]3[CH:37]4[CH2:43][CH2:42][CH:41]3[CH2:40][CH:39]([OH:45])[CH2:38]4)=[O:17])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: OC1CC2CCC(C1)N2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Temperature: 0 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.82 g, 0.00357 mol) in dry DMF (8.0 mL) was added with stirring HOBt (0.578 g, 0.00428 mol), DIPEA (1.9 mL, 0.0107 mol), 8-azabicyclo[3.2.1]octan-3-ol (0.5 g, 0.00393 mol) and the mixture was cooled to 0° C. To the resulting mixture was added EDCl (0.82 g, 0.00428 mol) and stirred for 15 h at ambient temperature. The reaction mixture was then diluted with ice water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×50 mL) and saturated brine solution (50 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording (1.1 g, 98%) of [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)methanone. MS-ESI m/z 341 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:37])[CH2:31][CH2:30]3)=[CH:26][CH:27]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c(OC2CCN(c3ccc(CN4CCNCC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(Cc2ccc(N3CCC(Oc4nc(-c5ccncn5)cc(=O)n4C)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 1-methyl-2-[1-(4-piperazin-1-ylmethyl-phenyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one (80 mg, 0.17 mmol), formaldehyde solution (37% in water, 55 mg, 0.68 mmol) and acetic acid (one drop) in 1,2-dichloroethane (0.85 ml) was added sodium triacetoxyborohydride (130 mg, 0.61 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=95/5) to afford 1-methyl-2-{1-[4-(4-methyl-piperazin-1-ylmethyl)phenyl]piperidin-4-yloxy}-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (49 mg, 0.10 mmol, 59%)
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]12[CH2:21][C:18]([CH2:22][NH2:23])([CH2:19][CH2:20]1)[CH2:17][CH2:16][CH2:15]2>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:23][CH2:22][C:18]23[CH2:21][N:14]([CH2:20][CH2:19]2)[CH2:15][CH2:16][CH2:17]3)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC12CCCN(CC1)C2
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CC1)C2
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A suspension of 4-amino-5-chloro-2-methoxybenzoic acid (1.72 g, 8.5 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1-carbonyldiimidazole (1.46 g, 9.0 mmol), stirred for one hour, then degassed under a stream of nitrogen for 10 minutes. A solution of 1-azabicyclo[3.2.1]octane-5-methanamine (1.27 g, 9.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added, and stirring was continued at room temperature for 18 hours and at 50° C. for one hour. The mixture was concentrated in vacuo and partitioned between toluene (100 mL) containing a little 2-propanol and saturated sodium carbonate (50 mL). The organic layer was separated and the organic solution was dried (Na2SO4). concentrated in vacuo, and triturated from cold ether. Recrystallization from acetonitrile (2 crops) afforded 1.92 g (70%) of colorless crystals; mp 185°-187° C.
Reaction SMILES: Br[CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CN(P(N(C)C)(N(C)C)=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC>[C:23]1([NH:22][CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Br)C(C)O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(Nc1ccccc1)C(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of ethyl 2-bromo-3-hydroxybutanoate (10 g) and 15 ml of HMPT is added 13.2 g of aniline. The reaction is stirred at RT for 3 days and then taken up in ether followed by washing with dilute sulfuric acid, pH 3, and water. The ether phase is dried over magnesium sulfate and evaporated to yield ethyl 2-phenylamino-3-hydroxybutanoate, which is saponified using 1.6 g of sodium hydoxide, 40 ml of methanol and 20 ml of water with stirring overnight at RT. The acid 2-phenylamino-3-hydroxybutanoic acid (3.0 g) is reacted with m-phenoxybenzyl bromide (3.4 g) in HMPT (20 ml) and potassium carbonate (2.12 g) at 35° for a few hours and worked up using ether/water to yield the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoic acid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18](=[O:26])[C@H:19]([CH3:25])[NH:20][C:21](=O)[CH:22]=[CH2:23])[CH3:16].[OH-].[K+]>C(Cl)(Cl)Cl>[CH2:15]([O:17][C:18]1[O:26][C:21]([CH:22]=[CH2:23])=[N:20][C:19]=1[CH3:25])[CH3:16]
Reactant: C=CC(=O)N[C@@H](C)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=Cc1nc(C)c(OCC)o1

Procedure:
To a suspension of 1.0 mole of phosphorus pentoxide in 300 ml. of dry chloroform is added dropwise with stirring a solution of 0.5 mole of N-acryloylalanine ethyl ester. The reaction mixture is heated at genetle reflux for 5 hours and then cooled. To the cooled mixture is added with rapid stirring 750 ml. of 20% aqueous potassium hydroxide. After stirring at room temperature for 1 hour, the chloroform layer is separated and the aqueous layer extracted with 2×200 ml. of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate, and concentrated in vacuo to yield 5-ethoxy-4-methyl-2-vinyloxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([C:28]1[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[CH:32]=1)[CH:24]=[CH:23][CH:22]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[CH2:12][CH:13]([O:15][CH3:16])[CH2:14]2)=[O:10])[CH:6]=[CH:5][C:4]=1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([C:28]1[CH:29]=[N:30][N:31]([CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[CH:32]=1)[CH:24]=[CH:23][CH:22]=2
Reactant: COc1cc(C(=O)N2CC(OC)C2)ccc1Nc1cc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1Nc1cc2c(-c3cnn(C4CCNCC4)c3)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-(4-(3-((2-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl)-amino)isoquinolin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 3, 23 mg, 0.038 mmol) in DCM (8 mL) at 0° C. was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. The solvents were removed in vacuo and the residue was purified by SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as yellow oil (19 mg, 98%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C([O-])=O)[CH2:21][CH:20]2[C:28](=[O:40])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:41]>CO>[ClH:41].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[C:28](=[O:40])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc2ccccc2c1)C1CN(C(=O)[O-])CCC1c1ccc(OCCCOCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccc2ccccc2c1)C1CNCCC1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 22 (l), from tert-butyl 3RS,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-yl-acetyl)-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained [(3RS,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yl]-2-naphthalen-2-yl-ethanone hydrochloride (1:1) in in the form of colourless crystals; MS: 494 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18]=[O:19]>CN(C=O)C>[OH:19][CH2:18][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[N:10]
Reactant: CCCCCC(C#N)c1ccc(F)cc1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)(CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
The crude (4-fluorophenyl)heptanenitrile obtained in stage 9-1-1 is added to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes, 8.9 g (296 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 3 hours and then hydrolysed with ice and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 8/2 heptane/ethyl acetate). 3.85 g in the form of a pale yellow oil are obtained with a yield of 44%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC.Cl>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:34](=[O:36])[CH3:35])=[CH:3][CH:4]=[C:5]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 78, tributyl(1-ethoxyvinyl)tin (157 mg, 0.436 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added tetrakis(triphenylphosphine) palladium (0) (38 mg, 0.0327 mmol). The reaction vessel was sealed and the mixture was stirred at 110° C. for 2 h. After cooling to rt, 2 M aq HCl (0.5 mL) was added, and the mixture was stirred at rt for 1.5 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford crude 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone. The crude product was triturated with Et2O and the solid was collected by filtration and dried to afford 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone (19 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 7.26-7.39 (m, 2H), 5.55 (s, 2H), 4.77 (d, J=4.9 Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.74 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([OH:13])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:3]2[O:14][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:13][C:4]=2[C:5]([Cl:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)c(O)c(O)c1Cl
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
A mixture of 1.0 g (3.5 mmol) of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate and 7.5 ml of dichlorodiphenylmethane is held at 150° C. under argon for 21/2 minutes. After rapid cooling the product is crystallized from n-pentane. There are obtained 1.3 g of methyl 7-bromo-4-chloro-2,2-diphenyl-1,3-benzodioxol-5-carboxylate as white crystals of melting point 137°-138° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]([OH:22])[CH2:12][NH:13][CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:40]1[C:44]2[CH:45]=[CH:46][C:47]([S:49](Cl)(=[O:51])=[O:50])=[CH:48][C:43]=2[O:42][CH2:41]1>C(Cl)Cl>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:11]([OH:22])[CH2:12][N:13]([S:49]([C:47]2[CH:46]=[CH:45][C:44]3[O:40][CH2:41][O:42][C:43]=3[CH:48]=2)(=[O:50])=[O:51])[CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc2c(c1)OCO2
Yield: 73.4 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid[1,3]dioxan-5-yl ester (0.059 g, 0.14 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.075 ml, 0.42 mmol) and Benzo[1,3]dioxole-5-sulfonyl chloride (0.037 g, 0.17 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% to 3% MeOH in CH2Cl2) gave 0.062 g of a white solid. MS(ES): 604 (M+1).