Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CCOCC>C1(C)C=CC=CC=1.C(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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH3:27]
Reactant: Cc1ccccc1B(O)O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (1 g) in toluene (6 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added saturated aqueous sodium hydrogen carbonate solution (3 ml) and a solution of 2-methylphenylboronic acid (0.610 g) in ethanol (3 ml). The mixture was heated under reflux for 24 hours, cooled and then poured into ether (60 ml) and water (80 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (60 ml). The combined organic layers were washed with water (2×50 ml), brine (50 ml) and then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with ether:hexane (3:2). Combination and evaporation of suitable fractions gave the title compound as a pale brown crystalline solid, m.p. 199-202° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Br
Yield: 72 %

Procedure:
4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-trifluoromethylbenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 155°-158° C., yield 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccccc1CCCBr
Reaction time: 12 h
Yield: 62.3 %

Procedure:
Compound 14-1 (3.10 g) was dissolved in methylene chloride (70 ml), triphenylphosphine (5.28 g) and N-bromosuccinimide (3.58 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.67 g) as a pale-yellow oil.
Reaction SMILES: [OH-].[K+].COC([C:7]1([C:20]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O.O1CCOCC1>O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(Cl)ccc23)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 4,7-Dichloroquinazoline (800 mg, 4 mmol) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.2 g, 5.2 mmol), as prepared in Example 1a, in a sealed vial at rt was added drop-wise a 1 M solution of LiHMDS in THF (6 mL, 6 mmol). The mixture was stirred at rt overnight. It was then quenched with aqueous NaH2PO4 and the mixture was extracted with DCM. The DCM layer was drawn off, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 2.2 g (>100%) of crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a) as a yellow semi-solid which was used as such for the next step. Solid KOH (224 mg, 4 mmol) was added to a suspension of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a; 41 mg, 0. 1 mmol) in a 1:1 mixture of dioxane and water (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (3b). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine (3c) as a di-HCl salt.
Reaction SMILES: [CH2:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])[CH3:2].[OH-].[Na+].O.S([O-])([O-])(=O)=O.[Al+3:19].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3]>O>[CH2:1]([P:3](=[O:7])([O-:10])[O:4][CH2:5][CH3:6])[CH3:2].[Al+3:19].[CH2:5]([O:4][P:3]([CH2:1][CH3:2])(=[O:7])[O-:10])[CH3:6].[CH2:5]([O:4][P:3]([CH2:1][CH3:2])(=[O:7])[O-:10])[CH3:6]
Reactant: CCOP(=O)(CC)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)([O-])CC
Yield: 100.7 %

Procedure:
Aluminum ethyl ethylphosphonate was prepared according to a known procedure: Diethyl ethylphosphonate (414 g), sodium hydroxide (199.5), and water (2.4 L) were refluxed for 4 h. A solution of aluminum sulfate hydrate (261 g) in water (830 mL) was then slowly added to form a white slurry. After filtration and drying, 319.7 g of aluminum ethyl ethylphosphonate was obtained as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>ClCCl>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:26])[CH3:27])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)n1ncc(NCC(O)CO)c(Cl)c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CNc2cnn(C(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.60 g of p-toluenesulfonyl chloride was added to a mixture comprising 2.09 g of 4-chloro-5-(2,3-dihydroxypropylamino)-2-i-propyl-3(2H)pyridazinone prepared in Reference Example 6, 12 ml of pyridine and 20 ml of dichloromethane, under cooling with ice. The mixture was stirred for 6 hours, and then left to stand for 2 days in an ice chamber. The reaction mixture was acidified to a pH of about 2 by adding cooled dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a colorless oily substance. The oily substance was purified by silica gel column chromatography, and 2.45 g of the above identified compound was obtained as a colorless viscous oily substance from the eluate with choroform-methanol (25:1, v/v).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][C:13]([CH2:36][O:37][CH3:38])=[N:12]1)([CH3:10])[CH3:9].Br[CH2:40][C:41]([NH2:43])=[O:42].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl.O>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:40][C:41]([NH2:43])=[O:42])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][C:13]([CH2:36][O:37][CH3:38])=[N:12]1)([CH3:10])[CH3:9]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Yield: 44 %

Procedure:
A suspension of 2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetate salt (99 mg, 0.18 mmol) in THF (1.8 mL) was treated with 2-bromoacetamide (109 mg, 0.2 mmol) followed by potassium carbonate (56 mg, 0.41 mmol) and the reaction mixture stirred at RT before being diluted with DCM and water. The aqueous layer was extracted twice with DCM and the combined organic extracts washed with saturated aqueous sodium bicarbonate followed by brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was dissolved in methanol, the solution cooled to 0° C. and treated with water to form a precipitate which was filtered off and washed with cold methanol/water to give a white solid. The solid was azeotroped with methanol then diethyl ether to give 308 as a white solid (38 mg, 43%). LCMS: RT=2.66 min, [M+H]+=480. 1H NMR 400 MHz (DMSO-d6) δ: 8.39 (1H, d, J=8.32 Hz), 8.16 (1H, s), 7.09-7.08 (1H, m), 6.97 (1H, s), 5.76-5.74 (1H, m), 4.58 (4H, d, J=14.42 Hz), 4.51 (2H, s), 3.96 (2H, s), 3.60 (2H, d, J=11.71 Hz), 3.37 (3H, s), 3.20 (2H, m), 2.86 (1H, m), 2.03 (4H, m), 1.53 (6H, d, J=6.57 Hz)
Reaction SMILES: [NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:2]([C:30]([OH:32])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O[N:41]1[C:46](=[O:47])[CH2:45][CH2:44][C:42]1=[O:43].CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:2]([C:30]([O:32][N:41]1[C:46](=[O:47])[CH2:45][CH2:44][C:42]1=[O:43])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reaction time: 48 h
Yield: 86.9 %

Procedure:
To a solution of Boc-(D)-Arg(Cbz2)—OH (1 g, 1.8 mmol) in CH2Cl2 (10 mL) was added HOSu (466 mg, 4.06 mmol), DIEA (1 mL) and EDC (846 mg, 4.4 mmol). The solution was stirred for 48 h. The solvent was evaporated and residue was dissolved in EtOAc (50 mL) and water (10 mL). The separated organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1 M HCl (10 mL) and sat. NaCl (3×10 mL). The organic layer was dried over MgSO4, filtered and evaporated. The oily residue was either used directly in Example 4 without further purification or purified by flash column over silica gel (50% EtOAc in hexane) to give Boc-(D)-Arg(Cbz2)-OSu (1 g, 85% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 40 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (100 mg, 0.24 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.74 mmol, 0.74 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.26 mmol, 38 mg). After 16 h, filtration of the precipitate and trituaration with Et2O gave the product (50 mg, 40%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.43-1.51 (br s, 3H, CHCH3), 2.49-2.57 (2 m, 4H, piperazine N(CH2)2), 3.01 (s, 6H, N(CH3)2), 3.69 (br, 5H, piperazine N(CH2)2 & CHCH3), 6.82 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.48 (s, br, 2H, pyridine H-3 & H-5), 8.00 (d, J=8.7 Hz, 2H, N,N-dimethylaminophenyl), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.61 (s, br, 2H, pyridine H-2 & H-6), 13.18 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:8]=[CH:7]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:9]2[N:8]=[CH:7][NH:6][C:10]=2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2cnc(-c3ccc(F)cc3)c2-c2ccnc(NC(N)=O)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2[nH]cnc2-c2ccc(F)cc2)ccn1
Yield: 96 %

Procedure:
To the solution of {4-[3-(2,4-Dimethoxy-benzyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridin-2-yl}-urea (Example 51, 15 mg, 0.034 mmol) in DCM (1.0 mL) is added trifluoroacetic acid (0.1 mL). The reaction mixture is stirred for 6.5 days at room temperature before saturated NaHCO3 aqueous solution (2 mL) is added along with water (10 ml). The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried and concentrated to give the crude product. Purification by silica flash column chromatography using 10% MeOH in DCM affords 9.7 mg of the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CCCCCC.C([Li])CCC.Cl[P:21]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([P:21]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1ccc(P(Cl)c2ccc(C)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(P(c2ccc(C)cc2)c2cccc(C)n2)cc1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
After dissolving 2-bromo-6-methylpyridine (23.5 mmol) in 40 ml of tetrahydrofuran, the mixture was cooled in a dry ice-ethanol bath, 1.59 M hexane solution of n-butyllithium (23.5 mmol) was added dropwise while stirring, and stirring was continued for 10 minutes to obtain a reaction mixture. To the obtained reaction mixture there was added chlorobis(4-methylphenyl)phosphine (17.5 mmol) dissolved in 40 ml of tetrahydrofuran, and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, purification was performed twice by silica gel column chromatography (developing solution: hexane/ethyl acetate=5/1, 9/1), to obtain 2.68 g of bis(4-methylphenyl)(6-methyl-2-pyridyl)phosphine (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].ClC(N(C)C)=C(C)C.[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:29]=[C:30]([NH2:37])[C:31]4[CH:32]=[N:33][NH:34][C:35]=4[CH:36]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH:37][C:30]1[CH:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][NH:19]3)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2)=[O:8]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cn1ncc(Cl)c1C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(Cl)c1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A solution of 4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (available from Fluorochem) (50 mg) in dry DCM (10 ml) was treated with 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.041 ml) (available from Acros) and allowed to stir at 20° C. for 10 min when a solution of 6-(1H-indol-4-yl)-1H-indazol-4-amine (77 mg) and triethylamine (0.043 ml) in DCM (5 ml) was added and the mixture stirred at 20° C. for 18 h. The mixture was poured onto an aminopropyl SPE cartridge (1 g) and allowed to stand for 2 h, then the mixture was eluted with methanol (5 ml) and blown to dryness under a stream of nitrogen. The crude product was purified by mass directed preparative HPLC (Method A) to give the title compound as a white solid (15 mg).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:37])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[CH:30]=[CH:29]3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[CH:30]=[CH:29]3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:37])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (406) (210 mg, 0.42 mmol) in dichloromethane (30 mL) was added triphenyl phosphine (550 mg, 2.09 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1.26 mmol) at room temperature and stirring was continued for 10 min (TLC, 5% methanol in ethyl acetate, Rf=0.2). The reaction mixture was concentrated under reduced pressure to get a crude product, which was purified by Prep-TLC plate (mobile phase 5% methanol in ethyl acetate) to get 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) (60 mg, 30%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].CO>O1CCCC1>[OH:14][CH2:13][C@H:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 25.0 g of N-α-t-BOC-D-proline in 250 ml of tetrahydrofuran which is cooled to 0° C. is added dropwise 15 ml of 10M borane-methyl sulfide complex. The reaction is kept at around -20° C. during the addition followed by warming to room temperature and then is gently refluxed for one hour. The mixture is cooled to 0° C., 250 ml of methanol is added carefully and the reaction is evaporated in vacuo to give 23.3 g of a colorless oil which crystallizes on standing to a colorless solid, mp 50°-53° C., [α]D26° =+47°±1 (C=1.162%, methylene chloride).
Reaction SMILES: C([O:3][C:4](=[O:50])[C@@H:5]([O:47][CH2:48][CH3:49])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26]/[CH:27]=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=3)[CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:39]([C@@H:38]([O:44][CH2:45][CH3:46])[CH2:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29]/[CH:28]=[CH:27]/[C:26]#[C:25][C:21]2[CH:20]=[C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:47][CH2:48][CH3:49])[C:4]([OH:50])=[O:3])=[CH:12][CH:11]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:36][CH:35]=1)([OH:41])=[O:40]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[5-(3-{5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (example 5) (130 mg 0.2 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (1.5 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a crystalline product. The product was recrystallised from tetrachloromethane and petroleum ether to give 72 mg (58%) of the title compound.