Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CO.O.O[Li].O>C1COCC1>[F:33][C:31]([F:32])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][CH2:22][C:21]([NH:20][CH:18]1[CH2:17][N:16]([CH:13]2[CH2:14][CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:19]1)=[O:36])=[O:35]
Reactant: COC(=O)c1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 50 °C

Procedure:
A solution of 4-(4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-benzoic acid methyl ester (less polar fraction from Example 9, 250 mg, 0.48 mmol) in THF (1 mL), MeOH (1 mL) and H2O (1 mL) was treated with LiOH.H2O (50 mg, 1.2 mmol) at room temperature. The reaction was then heated to 50° C. for 2 hours. The reaction was allowed to cool and solvent was removed in vacuo. 1 N HCl solution was added to adjust the solution to pH=6˜7. The white precipitate was collected by filtration and washed with water. The solid was dried in vacuo, re-dissolved in ethyl acetate and re-crystallization to afford the title compound.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:12]C1(C)CCCCC1=O.C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.IC(C)C>>[CH:1]([CH:4]1[C:8](=[O:9])[C:7]([CH3:10])([CH3:11])[CH2:6][CH2:5][CH2:12]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1CCC(C)(C)C1=O
Reactant: CC1(C)CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)I
Product: CC(C)C1CCCC(C)(C)C1=O
Yield: 78 %

Procedure:
As described in Example 3 for preparation of 5-isopropyl-2,2-dimethylcyclopentanone, from 2,2-dimethylcyclohexanone (12.6 g, 110 mmol), lithium diisopropylamide solution (2 M in THF, 55.0 ml, 110 mmol), DMPU (14.1 g, 110 mmol) and 2-iodopropane (25.5 g, 150 mmol), 6-isopropyl-2,2-dimethylcyclohexanone (13.1 g, 78%) was obtained after standard workup and purification by silica gel FC (pentane/Et2O, 6:4, Rf=0.26).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:5]([C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:17])[CH3:16])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].Cl[CH2:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:5]([C:7]1[N:12]([CH2:31][C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:40]3=[O:49])[CH:33]=2)[C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:16])[CH3:17])=[O:6]
Reactant: Cc1cc(CCl)cc(N2C(=O)c3ccccc3C2=O)n1
Reactant: Cc1cc(Cl)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C)nc(N3C(=O)c4ccccc4C3=O)c2)c1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a stirred solution of 6-(3-Chloro-5-methyl-benzoyl)-5-isopropyl-1 H-pyrimidine-2,4-dione (306 mg, 1 mmol), anhydrous powdered potassium carbonate (134 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 ml) at room temperature, was added 2-(4-Chloromethyl-6-methyl-pyridin-2-yl)-isoindole-1,3-dione (286 mg, 1 mmol). After stirring for overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1)) to afford 250 mg (45%) of a white solid. 1H NMR (200 MHz, CDCl3) δ 1.14 (3H, d, J=6.8 Hz), 1.21 (3H, d, J=6.8 Hz), 2.25-2.32 (4H, m), 2.46 (3H, s), 4.51 (1H, d, J=16.0 Hz), 5.14 (1H, d, J=16.0 Hz), 6.84 (1H, s), 6.94 (1H, s), 7.33 (1H, s), 7.37 (1H, s), 7.64 (1H, s), 7.76-2.83 (2H, m), 7.90-7.96 (2H, m), 9.19 (1H, s).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[OH-].[K+]>CS(C)=O.O>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][O:9][N:8]=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCCl
Reactant: ON=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCON=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of diphenyl-methanone oxime (2 g, 10 mmol) and (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.5 g, 10.4 mmol) in DMSO (20 ml) was added powdered potassium hydroxide (800 mg, 14.3 mmol) and the reaction mixture stirred overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed thoroughly with water and brine, then dried over anhydrous sodium sulphate and filtered. Concentration of the organic layer under reduced pressure gave diphenyl-methanone O-(2-dimethylaminoethyl)-oxime (700 mg, 26%) as a solid.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:16]([NH:19][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1)[C:17]#[CH:18]
Reactant: O=C(Nc1nnn[nH]1)c1ccc(F)cc1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1ccc(C(=O)Nc2nnn[nH]2)cc1

Procedure:
A mixture of 20 g (0.097 mol) of 4-fluoro-N-1H-tetrazol-5-ylbenzamide, 12.8 ml (0.193 mol) of propargylamine, 5.6 g of anhydrous potassium fluoride, and 13 g of potassium carbonate, in 320 ml of dimethylsulfoxide is heated at 50°-70° C. for six to twenty hours. The reaction is poured into water and the precipitate is collected, washed with water, and dried in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)COCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butoxy)acetate (step 4)(20 mg, 0.042 mmol) in DCM (0.5 ml) was treated with TFA (0.5 ml, 6.49 mmol) and stirred at RT for 1 h. The solvent was removed in vacuo and the crude product was dissolved in DCM (with <10% MeOH) and basified with saturated sodium bicarbonate solution. The organic portion was separated and the aqueous was extracted with 10% MeOH/DCM. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:20]=[C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=2[O:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:25]3[C:24]4[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=4[O:22][C:21]3=[O:20])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: N#Cc1ccc2[nH]c(=O)oc2c1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C#N)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (190 mg, 0.625 mmol, 1 eq), 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48) (100 mg, 0.625 mmol, 1 eq), cesium carbonate (400 mg, 1.23 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water and purified with flash chromatography to give 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH3:24])[CH:16]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]2=[O:25])=[CH:16][C:17]=1[CH3:24]
Reactant: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1N
Yield: 94.1 %

Procedure:
A solution of 4-(benzyloxy)-1-(3-methyl-4-nitrophenyl)pyridin-2(1H)-one (0.940 mg, 2.79 mmol) in EtOH (19.2 mL) and H2O (4.8 mL) was treated with iron powder (1.35 g, 24.2 mmol) and NH4Cl (64.1 mg). After stirring at reflux for two hours, the reaction mixture was filtered through Celite and the filtrate concentrated to yield the title compound (0.804 g, 94%) as an off-white solid 1H NMR (500 MHz, DMSO-d6) δ 7.45-7.34 (m, 6H), 6.85 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.00 (dd, J=7.5, 5.0 Hz, 1H), 5.90 (d, J=2.0 Hz, 1H), 5.11 (s, 2H), 5.03 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:31]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH:32]2[CH2:38][CH3:39]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:39][CH2:38][CH:32]2[CH2:33][CH:34]3[CH2:37][CH:31]2[CH2:36][CH2:35]3)[N:10]=[CH:9]1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCC1CC2CCC1C2
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(CCCOCCC2CC3CCC2C3)c[nH]1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-(bicyclo[2.2.1]hept-2-yl)ethane chloride are treated as described in Example 5.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[N:13]=[C:14]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:22])[S:15][C:16]=1[C:17](O)=[O:18]>>[CH3:11][C:12]1[N:13]=[C:14]([NH:20][C:21](=[O:22])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[S:15][C:16]=1[C:17](=[O:18])[NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Reactant: NCCCc1ccccc1
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCCCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 3-phenylpropylamine in place of benzylamine to react with 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid, the title compound was obtained as a white solid in 22% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.78-8.76 (m, 2H), 8.13-7.93 (m, 3H), 7.27-7.11 (m, 5H), 3.32-3.11 (m, 2H), 2.70-2.46 (m, 5H), 1.84-1.72 (m, 2H); MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1/[C:19](/[CH3:22])=[CH:20]\[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1/[C:19](/[CH3:22])=[CH:20]\[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C(/C)c1cc(C(=O)OC)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C/C=C(/C)c1cc(C(=O)O)ccc1OCc1ccccc1
Yield: 81.5 %

Procedure:
Methyl (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoate (592 mg, 2.0 mmol) was dissolved in methanol (20 ml), a solution of potassium hydroxide (336 mg, 6.0 mmol) in water (7 ml) was added and the mixture was stirred and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with dichloromethane, the organic layer was separated and the solvent removed in vacuo to afford (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoic acid (460 mg, 82%) as a colourless solid. 1H NMR (DMSO-d6) 7.85 (1H, dd), 7.57 (1H, d), 7.40 (4H, m), 7.34 (1H, m), 7.18 (1H, d), 5.57 (1H, q), 5.21 (2H, s), 1.96 (3H, s), 1.40 (3H, d). MS: [M+H]+ 283.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:21])[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O1CCOCC1>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: CC1CCN(C(=O)OC(C)(C)C)CC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
1-Benzyl-4-tert-butyloxycarbonyl-7-methylene-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (160 mg, 0.41 mmol) was stirred under an atmosphere of hydrogen in the presence of 10% palladium on charcoal (20 mg) in dioxan (5 ml) at room temperature for 20 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness affording the product. (160 mg, 100%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([N:14]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[C:15]2[C:20]3[S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([N:14]([C:15]2[C:20]3[S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:19]=3[CH:18]=[CH:17][CH:16]=2)[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(N(c2cccc3c2sc2ccccc23)c2cccc3c2sc2ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(N(c2cccc3c2sc2ccccc23)c2cccc3c2sc2ccccc23)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
N-(dibenzo[b,d]thiophen-4-yl)-N-(4-methoxyphenyl)dibenzo[b,d]thiophen-4-amine (4.6 g, 9.4 mmol) was dissolved in 100 mL of anhydrous dichloromethane. The solution was cooled with a dry ice/isopropanol bath. To the solution was added boron tribromide solution in hexanes (1.0 M solution, 16 mL). The reaction was allowed to warm to room temperature for 6 h. The reaction was quenched with water. The product was purified with column chromatography using dichloromethane as eluent. 4 g of desired product was obtained. (90% yield)
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:12]([CH3:13])[N:4]([CH:1]5[CH2:2][CH2:3]5)[N:5]=4)[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: OCc1ccc(Br)cn1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)cn4)cc3=O)ccc2nn1C1CC1
Reaction time: 3 h
Yield: 42.4 %

Procedure:
To a suspension of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (67 mg) and triphenylphosphine (140 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (125 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (34 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(O)C>[Cl:1][C:2]1[C:3]2[C:10]([C:21]3[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)n1cc(I)c2c(Cl)ncnc21
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)n1cc(-c2ccc([N+](=O)[O-])cc2)c2c(Cl)ncnc21
Temperature: 105 °C

Procedure:
A mixture of 4-chloro-5-iodo-7-isopropylpyrrolo[2,3-d]pyrimidine (0.57 g), 4-nitrophenylboronic acid (0.30 g), bis(triphenylphosphine)palladium (II) chloride (0.126 g), toluene (15 ml), ethanol (2 ml), water (4 ml) and sodium bicarbonate (0.45 g) was heated under nitrogen at 105° C. for 8 hours. The mixture was cooled to ambient temperature and then partitioned between brine (50 ml) and ethyl acetate (50 ml). The aqueous layer was further extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, dried, filtered and evaporated to leave a solid which was purified by flash column chromatography on silica using cyclohexane with increasing amounts of ethyl acetate as the mobile phase to give 4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)[OH:13]>C(OCC)(=O)C.C(O)C.[C].[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([CH:12]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)[OH:13])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(O)c1cc(C)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N)ccc1C(O)c1cc(C)ccn1
Yield: 33.2 %

Procedure:
(2-methoxy-4-nitrophenyl)(4-methylpyridin-2-yl)methanol (2.2 g) was dissolved in ethyl acetate (50 ml) and ethanol (50 ml), and the solution was reduced by catalytic hydrogenation overnight with 10% palladium-carbon of 50% hydration (150 mg). The catalyst was removed, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give (4-amino-2-methoxyphenyl)(4-methylpyridin-2-yl)methanol (0.65 g) as pale yellow crystals.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][C:10]=1[OH:14]
Reactant: BrBr
Reactant: Oc1cccc(CN2CCOCC2)c1
Solvent: CC(=O)O
Product: Oc1cc(CN2CCOCC2)ccc1Br

Procedure:
3-(Morpholin-4-ylmethyl)phenol (9.65 g) in glacial acetic acid (60 ml) was treated over 2 h with bromine (2.88 ml) in acetic acid (8 ml), evaporated to near dryness, water (100 ml) added and basified with 0.880 ammonia, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated to dryness to give an oil, which was purified by column chromatography eluting with 1:1 ether/isohexane to give the desired product as an oil (4.75 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)=[O:18])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:30][C:26]3[C:25]([F:31])=[CH:24][C:23]([CH2:22][CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:28][C:27]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1Cc1cc(F)c(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 64.1 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.021 g, 0.10 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.024 g, 0.10 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17]Br)[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=CCCCBr)COC1(C)C
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CC(C)OP(=O)(CCCC=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C)OC(C)C

Procedure:
A solution of 19.9 g of bromide 4 according to d) in 60 ml of triisopropyl phosphite is heated at 130°-135° for 20 hours at 100 mbar. The excess reagent is distilled off at 60°/0.1 mbar, and the residue is chromatographed on 250 g of silica gel. Elution with hexane/ethyl acetate 1:1 yields 20.6 g of phosphonic acid ester 5, [α]D =-8.6° (c=0.8, CHCl3); C21H40NO6P; calculated: C 58.18%, H 9.30%, N 3.23%, P 7.15%; found: C 57.4%, H 9.3%, N 3.2%, P 7.5%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][C:33](O)=[O:34])[C:26]2=[N:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]5[S:18][CH:19]=[CH:20][N:21]=5)(=[O:14])=[O:15])=[CH:11][CH:12]=4)[CH2:5][CH2:6]3)=[O:34])[C:26]2=[N:27][CH:28]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)Cn1ccc2cc(Cl)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1ccc2cc(Cl)cnc21)N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Yield: 46.7 %

Procedure:
Synthesized according to general procedure 17, method C using THF as solvent. To a solution of 4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.35 g, 1.08 mmol) and 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (0.25 g, 1.19 mmol) in THF (6 mL) was added HATU (0.533 g, 1.40 mmol) followed by the addition of DIEA (0.279 g, 2.16 mmol) at 0° C. under inert atmosphere. The reaction was quenched with water after 15 minutes, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography using 0-3% methanol in DCM gave 4-(1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.26 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=3.5 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 5.25 (d, J=2.6 Hz, 2H), 4.44 (d, J=12.9 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.24 (t, J=11.7 Hz, 1H), 2.95-2.88 (m, 1H), 2.70 (t, J=11.7 Hz, 1H), 1.91-1.66 (m, 3H), 1.55-1.45 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=516.5; tR=1.57 min.