Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[I:15][C:16]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>N1C=CC=CC=1>[Br:23][C:21]1[CH:20]=[CH:19][C:17]([NH:18][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[C:16]([I:15])[CH:22]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cc1I)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled 30 mL vial containing a stirring bar and 4-trifluoromethoxybenzoylchloride (0.70 g, 3.12 mmol), 2-iodo-4-bromoaniline (0.837 g, 2.81 mmol) in 3 mL of anhydrous pyridine was added. The bath was then removed. The reaction solution was stirred at room temperature overnight and 50 mL of EtOAc was added. The resulting solution was poured into 100 mL of 10% aq. HCl. The layers were stirred and then the organic layer was separated and washed with water (2×50 mL), dried with Na2SO4 and concentrated, revealing the desired product. 1H-NMR (400 MHz, CDCl3): δ=7.37 (d, 8.4 Hz, 2HCF3OCCH), 7.53 (m, 1H, ICNCCH), 7.96 (d, 1.6 Hz, 1H, BrCCHCI), 8.8 (d, 8.8 Hz, 2H, CHCHCCOCF3), 8.21 (s, 1H, NH), 8.34 (d, 8.8 Hz, 1H, ICNCCHCH). MS (electrospray) 486 (MH+), 488 (MH++2).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([NH:14][C:15]1([C:30]([NH:32][C@@H:33]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH2:34][C:35](OC)=[O:36])=[O:31])[CH2:20][CH2:19][N:18]([C:21]2[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([C@H:33]([NH:32][C:30]([C:15]2([NH:14][C:12](=[O:13])[O:11][C:7]([CH3:9])([CH3:8])[CH3:10])[CH2:16][CH2:17][N:18]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19][CH2:20]2)=[O:31])[CH2:34][CH2:35][OH:36])=[CH:44][CH:43]=1
Reactant: COC(=O)C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
LiAlH4 (1.398 mL, 1.40 mmol) was added dropwise to (R)-methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 41) (779 mg, 1.40 mmol) in THF (40 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 20° C. for 3 hours. The reaction mixture was quenched with water (1 mL) and neutralised with 2M HCl. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. The pure fractions were combined and evaporated to give (R)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (160 mg, 21.63%) as a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[OH:4][CH2:3][C@H:2]([NH:1][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](CO)c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-2-amino-2-phenylethanol and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 519 (M+H).
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NC1C=C[C:49]([C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[C:33]([C:26]1[CH:27]=[N:28][C:29]2[C:24]([C:25]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[CH:23][C:22]([S:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([NH:10][C:9]1[CH:8]=[CH:7][C:49]([C:52]3[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=3)=[CH:48][CH:47]=1)=[O:12])(=[O:21])=[O:20])=[CH:31][C:30]=2[CH3:32])(=[O:34])[NH2:35]
Reactant: COC(=O)CCCc1ccc(-c2ccc(N)cc2)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COC(=O)CCCc1ccc(-c2ccc(NC(=O)c3cccc(S(=O)(=O)c4cc(C)c5ncc(C(N)=O)c(Nc6cccc(OC)c6)c5c4)c3)cc2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 29 in place of 8-aminooctanol. ES/MS calcd. for C42H39N4O7S+ 743.3. Found m/z=743.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH2:22]([OH:40])[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][CH2:37][CH2:38][CH3:39]>>[CH2:22]([O:40][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1)[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][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Product: CCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
The procedure is analogous to Example 1, and 2-fluorotetracene-5,12-dione is reacted with 1-octadecanol, the 2-n-octadecyloxytetracene-5,12-dione obtained is converted into the corresponding diacetate by reductive acetylation, and the latter is reacted with sulfur int eh presence of p-toluenesulfonic acid to form 2-n-octadecyloxytetracene-5,6,11,12-tetrathiotetracene. The individual reaction products have the following characteristic data:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>O>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cnc(C(=O)O)cn1
Temperature: 95 °C
Reaction time: 4.5 h

Procedure:
A solution of methyl 5-chloropyrazine-2-carboxylate (2.0 g, 11.63 mmol) in 2-methoxyethanol (20 mL) was treated with solid potassium carbonate (4.8 g, 34.8 mmol). The mixture was heated at 95° C. and was stirred at this temperature for 4.5 h. The mixture was dissolved in water (20 mL) and extracted with diethyl ether. The aqueous layer was neutralized with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-methoxyethoxypyrazine-2-carboxylic acid as a pale yellow solid powder: (1.89 g, 82.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=O.C([N:21](CC)CC)C.Cl.NO.ClC(Cl)(Cl)C(Cl)=O.[Cl-].[Na+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]#[N:21]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (353 mg, 1.14 mmol) in MeCN (11.4 mL) was added triethylamine (223 uL, 1.60 mmol) and hydroxylamine hydrochloride (95.2 mg, 1.37 mmol). The reaction was heated to 60° C. for 16 h. The reaction mixture was then cooled to room temperature and additional triethylamine (541 uL, 3.88 mmol) was added, followed by trichloroacetyl chloride (306 uL, 2.74 mmol) dropwise. After stirring 30 min at room temperature, the reaction was heated to 65° C. for 20 h. The reaction mixture was then cooled to room temperature and poured into saturated aqueous sodium chloride (100 mL). The aqueous fraction was extracted with ethyl acetate (3×75 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated onto silica gel. Purification by ISCO chromatography (10 to 40% ethyl acetate:hexanes) afforded 301 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=1.8 Hz, 1 H), 7.97 (d, J=8.3 Hz, 1 H), 7.75 (dd, J=1.9, 9.0 Hz, 1 H), 6.07 (dd, J=2.5, 9.1 Hz, 1 H), 3.97-3.60 (m, 2 H), 2.40-2.17 (m, 1 H), 2.12-1.91 (m, 2 H), 1.84-1.64 (m, 1 H), 1.66-1.47 (m, 2 H); HPLC tR=3.73 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([OH:23])[C@H:21]([OH:24])[C@@H:20]([CH2:25][O:26][CH3:27])[O:19]2)=[C:11]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[OH:23][C@@H:22]1[C@H:21]([OH:24])[C@@H:20]([CH2:25][O:26][CH3:27])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[N:10][C:11]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Methanesulfonyl chloride (27 mg, 0.22 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (120 mg, 0.23 mmol) (Example 11) and triethylamine (0.1 ml, 0.72 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2 hr when the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (98:2) increasing in polarity to (95:5). This gave the title compound (87 mg) as a powder. MS: 583 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18]O)[C@H:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)O[C:37](=O)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2)=O>ClCCl>[F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:4][C@@H:3]([C:32]3[C:31]4[C:36](=[CH:37][CH:5]=[CH:6][CH:7]=4)[CH:35]=[CH:34][CH:33]=3)[CH3:2])[CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COC(=O)c1cnc(N2CC[C@@H](CO)[C@H](c3ccccc3)C2)c(F)c1
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCC(CN[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(F)c1
Reaction time: 1.5 h
Yield: 154.1 %

Procedure:
To a solution of 282 mg of methyl rel-5-fluoro-6-[(3R,4R)-4-(hydroxymethyl)-3-phenylpiperidin-1-yl]nicotinate in 3.0 mL of dichloromethane was added 382 mg of Dess-Martin Periodinane at room temperature, followed by stirring for 1.5 hours. This reaction mixture was washed with 1,2-dichloroethane, transferred to a dropping funnel, and added dropwise to a mixture of 147 mg of (1R)-1-(1-naphthyl)ethaneamine, 521 mg of sodium triacetoxyborohydride, 49 mg of acetic acid, and 10 mL of 1,2-dichloroethane at room temperature. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by vigorously stirring for 10 minutes, and then extraction with chloroform. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel (FUJI SILISIA CHEMICAL. Ltd., Japan) column chromatography (hexane-ethyl acetate) to obtain 314 mg of methyl 5-fluoro-6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]nicotinate as a colorless foamy substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][CH:48]([F:58])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[N:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:58][CH:48]([F:47])[C:49]1[N:53]2[CH2:54][CH2:55][N:56]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH2:57][C:52]2=[N:51][N:50]=1
Reactant: FC(F)c1nnc2n1CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2C(F)F)C1
Reaction time: 12 h
Yield: 19.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (685 mg, 2.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.10 g, 3.45 mmol), crude 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 23d (400 mg, 2.30 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 23 (200 mg, yield 20.0%) as a white solid.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)=[O:31]>>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:21][CH:20]=1)=[O:31]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCCO)c1cc2ccccc2o1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCCNC(=O)c2cc3ccccc3o2)cc1
Yield: 51 %

Procedure:
The product of Example 2 (0.40 g, 1.24 mmol) was coupled to N-(4-hydroxybutyl)-1-benzofuran-2-carboxamide, prepared according to Example 17, (0.29 g, 1.24 mmol) using the procedure of Example 3 to provide 0.34 g (51% yield) of an off white powder. MP>200° C.; 1H NMR (DMSO-d6): δ1.35-1.62 (m, CH2, CH2), 1.9 (s, CH3), 3.20 (s, CH3), 3.32-3.41 (m, CH2, CH2), 7.0-7.1 (m, 4 Ar H), 7.35 (t, 1 Ar H), 7.45 (t, 1 Ar H), 7.54 (s, 1 Ar H), 7.65 (d, 1 Ar H), 7.77 (d, 1 Ar H), 7.92 (m, 3 Ar H) 8.8 (t, NH), Electrospray Mass Spec: m/z 537.2 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[C:44]2[O:43][CH:42]=[CH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[C:44]5[O:43][CH:42]=[CH:41][C:40]=5[CH:39]=[CH:38][CH:37]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2ccoc12
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1cccc2ccoc12
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzofuran-7-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of the product from step (i) (3.0 g), potassium carbonate (4.42 g) and benzyl bromide (3.90 ml) in DMF (40 ml) was heated at 90° C. for 14 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 5:1, yield 6.3 g.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1S[C:15](=[O:24])[CH2:16][CH2:17][C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>CCOCC.C1COCC1>[C:18]1([CH2:17][CH2:16][C:15]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C(CCC1=CCCCC1)Sc1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCC1=CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
Cyclopentylmagnesium bromide (1.6 mL, 3.15 mmol, 2M soln in ether) was added to a cooled −78° C. solution of 3-Cyclohex-1-enyl-thiopropionic acid S-pyridin-2-yl ester (0.65 g, 2.63 mmol, from Step 3) dissolved in THF (10 mL). The reaction mixture was stirred for 45 min at −78° C. and then warmed up to rt. The reaction was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound as a clear oil (0.39 g, 72%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:14][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH:1]=[O:16])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: C=Cc1ccc2c(c1)C(=O)N(C)CC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCc2ccc(C=O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of 7-ethenyl-2-methyl-3,4-dihydro-1(2H)-isoquinolinone (181 mg, 0.968 mmol) in 1,4-dioxane (I 5 ml) and water (3 ml) at 0° C. was added sodium periodate (476 mg, 2.226 mmol) and osmium tetroxide (1.1 ml of a 4% aqueous solution). The reaction mixture was warmed to room temperature and stirred for 0.5 h before evaporation of the reaction mixture. The residue was dissolved in 1,4-dioxane (20 ml) and evaporated again. The mixture was then dissolved in dichloromethane (100 ml), dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% Ethyl Acetate/Hexane, gave the product (136 mg, 74%).
Reaction SMILES: [Li].[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:7][CH2:6][CH2:5][O:4]1.[CH3:14][Li]>O1CCCC1>[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:14])[O:4][CH2:5][CH2:6][O:7]1
Reactant: [Li]C
Reactant: CC1(CCCC(=O)O)OCCO1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(=O)CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
348 Mg. of the lithium salt of the ketal acid, 4-(2-methyl-1,3-dioxolan-2-yl)butanoic acid was dissolved in 5 ml. anhydrous tetrahydrofuran. The solution was cooled to 0° C and 1.25 ml. of a 1.6 molar solution of methyllithium in dicthylether was added dropwise over a period of 1 hour while stirring under a nitrogen atmosphere. The solution was allowed to rise approximately to 20° C and kept at this temperature over a period of 2 hours. The reaction mixture as added to crushed ice and the organic solvents were removed in vacuo. The residue was extracted with ether, the extract was washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated in vacuo to give crude 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: Fc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(Br)c(Br)c4)ncnc3cn2)cc1
Temperature: 70 °C
Reaction time: 138 h
Yield: 94.5 %

Procedure:
A mixture of compound 207 (3.40 g, 8.54 mmol) and 4-methoxybenzylamine (11.2 mL, 85.4 mmol) in dry DMSO (22 mL) was stirred under a nitrogen atmosphere at 70° C. (bath temperature) for 138 h. The mixture was then cooled and poured into water (400 mL). Petroleum ether (400 mL) was added and stirred at room temperature for 30 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (400 mL). It was filtered and washed solid with water (3×30 mL). The sticky yellow/orange solid was stirred with acetone (100 mL) at room temperature for ca. 30 min. to give a fine orange precipitate. Water (200 mL) was added and stirred further at room temperature for 2 h. The solid was collected by suction-filtration, washed with water/acetone (2:1) (5×30 mL), and dried in vacuum over silica-gel/KOH to give pure N4-(3,4-dibromophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (216) (4.16 g, 95%) as a greenish yellow solid, mp 166-169° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.77 (s, 1H, 8.42 (s, 1H), 8.40 (br s, 1H), 7.89 (br d, J=7.7 Hz, 1H), 7.76 (d, J=8.7, Hz, 1H), 7.40-7.25 (m, 3H), 7.17 (s, 1H), 6.88 (br d, J=8.3 Hz, 2H), 4.49 (d, J=5.9 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C21H17Br2N5O.0.25hexane: C, 50.35; H, 3.85; N, 13.05%. Found C, 50.56; H, 3.54; N, 12.87%.