Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[NH:3][C:4]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 11 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 11% of theory; LC (method 4): tR=1.86 min; Mass spectrum (ESI+): m/z=334 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65][CH:64]=1>ClCCl>[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:11](=[O:12])[CH:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:65][CH:64]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCOCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C(CC2CCOCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
A solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (155 mg, 0.42 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (240 mg, 0.051 mmol), N,N-diisopropylethylamine (165 mg, 0.127 mmol) and 6-aminonicotinic acid methyl ester (80 mg, 0.51 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-[2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester (110 mg, 55%), as an off-white solid: LR-ES-MS m/z calculated for C25H25F2N3O6 [M]+ 501, observed [M+H]+ 502; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.95 (m, 7H) 3.11-3.32 (m, 2H) 3.70-3.92 (m, 2H) 3.86 (s, 3H) 4.37 (d, J=18.1 Hz, 1H) 4.64 (d, J=18.1 Hz, 1H) 4.98-5.12 (m, 2H) 7.30-7.51 (m, 3H) 8.13-8.20 (m, 1H) 8.28 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.33 (s, 1H).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32]12[N:39]([C:40](=[O:42])[CH3:41])[CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[C:40]([N:39]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][N:34]([C:22]([C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:14]3[N:15]=[CH:16][C:11]4[CH:10]=[C:9]([C:27]([N:28]([CH3:29])[CH3:30])=[O:31])[N:8]([CH:1]5[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:12]=4[N:13]=3)=[N:19][CH:20]=1)=[O:23])[CH2:35]2)(=[O:42])[CH3:41]
Reactant: CC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CC(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCCCC5)c4n3)nc1)C2
Yield: 88 %

Procedure:
Following general amide formation method 3, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 1-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanone which gave 2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (63 mg) in 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.69 (s, 1H) 8.90 (s, 1H) 8.72 (d, J=8.59 Hz, 1H) 8.51 (d, J=2.02 Hz, 1H) 7.78 (dd, J=8.84, 2.27 Hz, 1H) 6.46 (s, 1H) 4.71 (br. s., 1H) 4.51 (tt, J=11.12, 4.04 Hz, 1H) 4.16 (br. s., 1H) 3.24-3.10 (m, 7H) 2.70-2.55 (m, 2H) 2.18-2.06 (m, 4H) 2.01 (ddd, J=13.64, 7.07, 4.04 Hz, 4H) 1.95-1.79 (m, 5H) 1.79-1.62 (m, 5H) 1.62-1.49 (m, 2H). HR-MS (m/z MH+) 559.31 RT 3.89 min.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:23][C:2]([F:35])([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)COS(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN=[N+]=[N-])c2c1
Temperature: 95 °C
Yield: 119.5 %

Procedure:
To a solution of diethyl 1-(2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}propyl)-1H-indole-2,6-dicarboxylate (4.7 g, 59% pure, 5.5 mmol) in DMF (40 mL) is added sodium azide (908 mg, 13.8 mmol). The mixture is heated at 95° C. for 40 h. Water (250 mL) is added and the mixture is extracted with EtOAc (3×250 mL). The organic layers are combined, washed with water (3×250 mL), dried (Na2SO4) and concentrated to afford the title crude compound (2.5 g) which is used in the next step without purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:22]=[CH:21][C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH:14](O)[CH2:15][C:9]=2[CH:8]=1)(=[O:6])=[O:5].[Cl-].[Ca+2].[Cl-]>C1C=CC=CC=1>[Cl:1][CH:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11][C:10]2[CH:21]=[CH:22][C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])=[CH:8][C:9]=2[CH2:15]1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(O)c1ccccc1S2
Reactant: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Reaction time: 20 h

Procedure:
Hydrochloric acid gas is introduced at 10° C for 2 hours into a mixture of 12 g of 10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]thiepin-10-ol, 250 ml of benzene and 20 g of calcium chloride. The mixture is then left to stand at room temperature for 20 hours. The excess hydrochloric acid is driven off by the introduction of nitrogen. The mixture is filtered and evaporated under reduced pressure. 10-chloro-10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]thiepin is obtained.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:26]([C:21]1[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:20]=1[O:30][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:30][C:20]2[C:21]([C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(C)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 2,6-di-tert-butyl-4-methylphenol and triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:27][CH2:28][CH2:29][NH2:30])(=[O:26])[CH3:25]>>[C:24]([NH:27][CH2:28][CH2:29][NH:30][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH:11]=2)=[N:16][CH:17]=1)(=[O:26])[CH3:25]
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 48 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using N-acetylethylenediamine instead of ethanolamine, to the title compound (120 mg, 48%) which was obtained as a white solid. MS: m/e=413.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(Cl)(Cl)Cl>C(#N)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:4][C:5]#[C:6][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:28][CH2:27]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC#Cc3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
10.2 Grams of methyl 2-piperazinylethyl 2,6-dimethyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 4.5 g of 3-phenylpropargyl bromide in 100 ml of acetonitrile were stirred at 30° C. for 5 hours under heating condition. After the reaction was finished, chloroform was added to the reaction mixture, and the mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and water in this order, and dried with anhydrous sodium sulfate. The dried chloroform extract was concentrated by removing the solvent by evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane-methanol:dichloromethane =1:100). The product thus purified was then converted into a hydrochloride by adding hydrochloric acid-dioxane, and recrystallized from ethyl acetate-methanol-water to yield 1.2 g of methyl 2-[4-(3-phenyl-2-propynyl)-1-piperazinyl]ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in the form of light yellow needle-like crystals. Melting point: 217°-220° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33](C(OC(C)(C)C)=O)[N:32]=[CH:31]5)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:13]4[CH:12]=[C:11]([NH:10][C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[O:9])[CH:16]=[CH:15][CH:14]=4)[N:26]=3)=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CN1CCN(C(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)Nc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1

Procedure:
To tert-butyl 5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (165 mg, 0.22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (6 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was purified by prep HPLC (method 25-50_70 mins) to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylpiperazine-1-carboxamide. (88 mg, 69%)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19][CH2:20][C:21]#[N:22]>C1COCC1>[C:21]([CH2:20][S:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:1](=[O:3])[CH3:2])#[N:22]
Reactant: N#CCSc1ccc(F)cc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)ccc1SCC#N
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 86 %

Procedure:
Acetyl chloride (1.5 ml) in THF (10 ml) and subsequently pyridine (1.7 ml) in THF (10 ml) was added to a stirred solution of (2-amino-4-fluoro-phenylsulfanyl)acetonitrile (3.5 g) in THF (30 ml) at 0° C. The mixture was stirred at 0° C. for 50 min. Then the solvent was removed in vacuo and the residue was triturated with water (80 ml). The precipitate was filtered off and dried yielding 3.7 g (86%) of the title compound as yellow crystals; mp 113-115° C.; 1H-NMR (DMSO-d6), δ (ppm): 9.59 (s, 1H, NH), 7.73-7.57 (m, 2H, Ar—H), 7.19-7.05 (m, 1H, Ar—H), 4.05 (s, 2H, CH2), 2.12 (s, 3H, CH3). The title compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.FC(F)(F)S(O)(=O)=O>CC1C=CC(C)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][C:7]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C(=O)c2cc(C)ccc2C)cc1
Reaction time: 6 h
Yield: 135 %

Procedure:
A mixture of p-toluic acid (22.2 g, 0.163 mole), p-xylene (100 mL), and trifluoromethanesulfonic acid (5 mL; 0.056 mole) was heated at reflux for 21 hours in a 300 mL flask equipped with a Dean-Stark trap, after which time 3 mL of water had been collected in the trap. The progress of the reaction was measured by gas chromatography as well as by the amount of water collected. After 6 hours, 22% of starting material had been converted to 2,5,4'-trimethylbenzophenone. The mixture was extracted with water, with 5% aqueous sodium hydroxide solution, and again with water. Evaporation of the organic layer gave 24 g (0.11 mole) of 2,5,4'-trimethylbenzophenone, 66% of theory.
Reaction SMILES: C([C:5]([Br:17])(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)CCC.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:29]([O-])([O-:31])=[O:30].[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[S:29](=[C:5]([Br:17])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: CCCCC(Br)(CCCC)c1ccc(F)cc1
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)=C(Br)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH2Cl2 at 0° C. was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na2CO3, dried (MgSO4), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86, 5.64, 1H), 9.49 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([C:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=2)[C:14]([CH2:30][O:31][C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=2[CH3:41])=[C:13]([CH3:42])[N:12]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:12]=[C:13]([CH3:42])[C:14]([CH2:30][O:31][C:32]2[CH:37]=[C:36]([CH:38]([CH3:39])[CH3:40])[CH:35]=[CH:34][C:33]=2[CH3:41])=[C:15]([C:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=2)[N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCNCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (741 mg, 1.3 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. is added TFA (2 mL). The mixture is then stirred a room temperature for 16 h. After removal of the solvent and excess of TFA under reduced pressure, the residue is neutralized with sat. NaHCO3, and extracted with CH2Cl2. The extracts are dried over anhydrous MgSO4, concentrated and purified by silica gel column chromatography to provide the desired product. [mass expected (469.7); mass found (M+1: 470.6)].
Reaction SMILES: C(=[C:4]([CH:6]([CH2:8][OH:9])[OH:7])[OH:5])(C)C.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:24]([O:9][CH2:8][CH:6]([OH:7])[CH2:4][OH:5])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCBr
Reactant: CC(C)=C(O)C(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOCC(O)CO
Temperature: 0 °C
Yield: 70 %

Procedure:
Isopropylideneglycerol (solketal, 26.4 g, 0.20 mol) in 60 mL of tolune was added dropwise to a solution of powdered KOH (22.4 g., 0.04 mol) in 150 mL toluene. The resulting mixture was refluxed for 4 hours. 1-Bromododecane (50 g, 0.20 mol) in 40 mL of tolune was then added dropwise, and the solution was refluxed for 10 hours. After cooling, the reaction mixture was diluted with 200 mL of ice-water and extracted with diethyl ether (3×100 mL). The ether layers were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in 60 mL of diethyl ether and 260 mL of MeOH. Concentrated HCl (60 mL) was added, and the solution was refluxed for 16 hours. After cooling, ice-water (150 mL) was added, and the layers were separated. The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic fractions were then dried over sodium sulfate, filtered, and concentrated in vacuo. The solid residue was recrystallized from MeOH to give 37 g (0.14 mol, 71%) of a white solid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][OH:28])[O:18]1>>[CH3:15][O:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][O:28][C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=2[C:6]#[N:7])[O:18]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CO[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Product: CO[C@@H]1O[C@H](COc2cccc([N+](=O)[O-])c2C#N)[C@H]2OC(C)(C)O[C@@H]12
Yield: 70 %

Procedure:
Prepared as in Example 111c from 2,6 dinitrobenzonitrile and ((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol in 70% yield as white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 3H), 1.49 (s, 3H), 3.32 (s, 3H), 4.23 (d, J=2.0 Hz, 1H), 4.24 (s, 1H), 4.60 (br t, J=6.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 1H), 4.86 (br d, J=6.0 Hz, 1H), 5.01 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.87 (dd, J=0.8, 8.4 Hz, 1H).
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:5]=2[O:4][CH2:3]1.S(C)C.[NH4+].[Cl-]>C1COCC1>[O:4]1[C:5]2[C:11]([CH2:12][OH:13])=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][CH2:2][CH2:3]1
Reactant: O=C1COc2c(cccc2C(=O)O)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cccc2c1OCCN2

Procedure:
To a suspension of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid (1.51 g, 7.8 mmol) in anhydrous THF (10 mL) was added BH3.Me2S (2 M in THF, 10 mL, 20 mmol) dropwise under nitrogen at 0° C. The resulted mixture was allowed to rise to r.t., and the reaction was continued to be carried out at this temperature overnight. Then, saturated aqueous NH4Cl (30 mL) was added in, and the resulted mixture was extracted with EtOAc (200 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 solution (30 mL), brine (30 mL), dried (Na2SO4) and filtered before it was concentrated under reduced pressure. The resulted crude product (3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-methanol, which was utilized in the following step without further purification. MS m/z: 166.2 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 17 h
Yield: 91.8 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (2.0 g, 5 mmol), bis(triphenylphosphine)-Palladium dichloride (700 mg, 1 mmol) and CuI (100 mg, 0.5 mmol) were added to 14 mL dry THF under nitrogen. Trimethylsilyl acetylene (1.4 mL, 10 mmol) was added, followed by 7 mL diisopropylethylamine. The reaction mixture was stirred at 50° C. under nitrogen for 17 hours, then was allowed to cool for two hours with stirring. The reaction mixture was poured into 15% aqueous NHCl and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 150 g of flash silica (2%-4% MeOH/CH2Cl2) to give 1.70 g of 5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=371.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].[CH2:21]([Mg]Br)[CH3:22]>O1CCCC1>[CH2:21]([C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20])[CH3:22]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCN1CC(C)=C(CC)C2=C1N1CN(OC)C=C1C=N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7 g of intermediate A1 are suspended in 150 ml tetrahydrofurane. 30 ml of a solution of ethyl magnesium bromide in tetrahydrofurane (3 M) are added. The mixture is stirred for 4 hours at room temperature. After filtration the solvent is removed. The crude product is purified by preparative HPLC.