Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH2:16][CH2:17][CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH2:17][CH3:18])[N:11]=[CH:10]2)=[O:4]
Reactant: CCCI
Reactant: COC(=O)c1cc(Cl)cc2cn[nH]c12
Product: CCCn1ncc2cc(Cl)cc(C(=O)OC)c21
Yield: 39 %

Procedure:
Compound 16 was prepared following general method 1, using 5-chloro-1H-indazole-7-carboxylic acid methyl ester (WO2011008572) as a starting material and 1-iodopropane as alkylating agent. Yield: 39%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 636.24 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-])=O)=[CH:16][CH:15]=2)=[N:6]1>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][CH:15]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1ccc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
1.22 g (approx. 3.34 mmol, purity approx. 60%) of the compound from example 42A were initially charged in pyridine (149 ml) and then 505 mg (0.47 mmol) of palladium (10% on charcoal) were added. The mixture was hydrogenated under standard hydrogen pressure at RT overnight. The reaction mixture was then filtered through kieselguhr and the filtercake was washed with methanol. The filtrate was concentrated, methanol was added and the solids were filtered off. The filtrate was concentrated by rotary evaporation, the residue was chromatographed on silica gel (eluent: 5:1, 3:1 cyclohexane/ethyl acetate) and the product fractions were concentrated. This gave 491 mg (44% of theory) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[N+:13]([O-])=O.[OH-].[Na+]>>[NH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([Cl:9])=[C:6]([NH2:10])[CH:5]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(N)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 399 gm. (1.77 mole) of stannous chloride dihydrate in 975 ml. of concentrated hydrochloric acid is added 60 gm. (0.258 mole) of 1,5-dichloro-2,4-dinitrobenzene. The temperature rises to 72° and a solution occurs. The mixture is allowed to cool to room temperature and then cooled in an ice-bath (to 5°). A cold 50% solution of sodium hydroxide is added, with cooling, until the mixture is strongly basic. The mixture is filtered and the precipitate on the funnel washed four times with 500 ml. portions of ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous M9SO4 and the solvent removed. The residue is recrystallized from 50% ethanol-water. There is obtained 31.9 gm. (70%) of colorless needles melting at 142°-3°.
Reaction SMILES: [CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH2:25][OH:26])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:18][CH3:19])([O:10][Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[CH2:8][CH3:9])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].O[C:50]1[CH:51]=[C:52]([C:60]([O:62][CH3:63])=[O:61])[C:53](=[CH:58][CH:59]=1)[C:54]([O:56][CH3:57])=[O:55]>ClCCl.CC(=O)CC>[CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH2:25][O:26][C:59]2[CH:58]=[C:53]([C:54]([O:56][CH3:57])=[O:55])[C:52](=[CH:51][CH:50]=2)[C:60]([O:62][CH3:63])=[O:61])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:8][CH3:9])([O:10][Si:11]([CH2:16][CH3:17])([CH2:12][CH3:13])[CH2:14][CH3:15])[CH2:18][CH3:19])[CH3:2]
Reactant: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(CO)cs1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.9 g (9.8 mmol) of [5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-thienyl]methanol are dissolved in 100 mL of dichloromethane and the mixture is cooled to 0° C. 2 mL (15 mmol) of triethylamine are added, followed by 840 μL (10.7 mmol) of methanesulphonyl chloride. After stirring for 30 minutes, the medium is treated with ammonium chloride solution. The crude residue obtained is then dissolved in 100 mL of 2-butanone. 100 mg (0.7 mmol) of sodium iodide, 1.6 g (11.6 mmol) of potassium carbonate and 2 g (10 mmol) of dimethyl 4-hydroxyphthalate are added to this solution. The reaction medium is refluxed for 15 hours and then cooled and filtered through Celite. The residue obtained is purified by chromatography on a column of silica (eluent: 93 heptane/7 ethyl acetate). The desired product is obtained in the form of a colourless oil (m=1.7 g; Y=30%).
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Br:37][C:38]1[CH:39]=[N:40][C:41](F)=[C:42]([CH:54]=1)[C:43]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53])=[O:44].Cl.O1CCOCC1>CN1C(=O)CCC1>[ClH:1].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:41]4[N:40]=[CH:39][C:38]([Br:37])=[CH:54][C:42]=4[C:43]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=4[F:53])=[O:44])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cc(Br)cnc1F
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(F)cc1F)c1cc(Br)cnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
To a solution of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluoroaniline (17 mg, 0.07 mmol, Compound C of Example 1) and 5-bromo-N-(2,4-difluorophenyl)-2-fluoronicotinamide (26 mg, 0.08 mmol) in 1 mL of NMP was added 4N HCl in 1,4-dioxane (0.05 mL, 0.20 mmol). The mixture was stirred at 110° C. for 4 d. After cooling, the mixture was purified on preparative (RP) HPLC to give fractions containing the desired product. The fractions were pooled and concentrated in vacuo and the residue was treated with 10 mL of 1N HCl and it was concentrated again to give the title compound (8.0 mg, 18% yield). 1H NMR (DMSO-d6) δ 10.66 (s, 1H), 10.62 (s, 1H), 8.55 (d, 2H, J=7.5 Hz), 8.06 (d, 1H, J=13.4 Hz), 7.35-7.62 (m, 5H), 7.16 (m, 1H), 6.62 (d, 1H, J=6.0 Hz), 6.43 (s, 1H); MS(ESI+) m/z 554.15, 556.14 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[C:35]([CH:9]([P:4](=[O:3])([OH:5])[OH:8])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])#[N:36]
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(C#N)P(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of {1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was added TMSBr (180 μL, 1.38 mmol) and 2,6-lutidine (160 μL, 1.38 mmol). The reaction solution was allowed stir at room temperature for one hour before quenching with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg (60%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 1.86 (s,3H), 2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J=7.2 Hz, 2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 15.28 ppm; MS (m/z) 380 [M−H]−, 382 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[CH:7][CH:6]=1)=[O:4].Cl>CO>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([B:11]([OH:13])[OH:12])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(B(O)O)cc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
380 mg of sodium borohydride were added to a solution of 1.5 g of (4-formylphenyl)-boronic acid in 40 ml of methanol at 0° C. under an inert atmosphere, and after stirring for 30 minutes, 200 ml of 2N hydrochloric acid were added. After evaporation under reduced pressure, the crude product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, followed by filtration and evaporation under reduced pressure to obtain 1.5 g of the expected product with a Rf=0.15 (cyclohexane/ethyl acetate 50/50).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:27][CH2:26]1
Reactant: COC1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-methoxypiperidine (1.2 equiv) to give 215 (19.6 mg, M+1 411.1)
Reaction SMILES: Cl[C:2]1[C:3]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].CN(C)C(=O)C.O>Cl.CC(O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[C:3]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc2[nH]c3ncnc(Cl)c3c2c1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2[nH]c3ncnc(Nc4cccc(Br)c4)c3c2c1
Temperature: 120 °C
Yield: 28.5 %

Procedure:
A mixture of 4-chloro-6-methoxyindolo-[2,3-d]pyrimidine (107 mg, 0.37 mmol, 80% pure), 3-bromoaniline (0.15 mL, 1.4 mmol), N,N-dimethylacetamide (1 mL), and 1 drop of a solution of 2-propanol that is 8.5 molar in HCl is heated under N2 at 120° C. for 5 h. The solution is concentrated in vacuo to an oily solid that is triturated in 5% aqueous sodium bicarbonate. The solids are collected by filtration, then washed successively with H2O and EtOAc. The solids are warmed in a small volume of N,N-dimethylformamide and filtered. The filtrate is purified by thick layer silica gel chromatography eluting with 3:2 dichloromethane:EtOAc. The product band is collected and sonicated in EtOAc. The mixture is filtered and the filtrate is concentrated to a solid that is sonicated in MeOH. The solids are collected, washed with MeOH, and dried to give pure 4-(3-bromoanilino)-6-methoxyindolo[2,3-d]pyrimidine (39 mg, 28%) hydrated with 0.7 equivalent of H2O. 1H NMR (DMSO): δ11.99 (1H, br s, exchanges with D2O), 8.97 (1H, br s, exchanges with D2O), 8.44 (1H, s), 8.02 (1H, s), 7.91 (1H, d, J=2.4 Hz), 7.76 (1H, d, J=8.0 Hz), 7.42 (1H, d, J=8.7 Hz), 7.36-7.24 (2H, m), 7.08 (1H,dd, J=8.7, 2.2 Hz), 3.87 (3H, s).
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16](C(C)(C)C)[C:15]=1[OH:26].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[OH:26][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:3]1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: COc1cc(-c2cc(OC)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc(O)c(-c2cc(OC)ccc2O)c1
Temperature: 40 °C

Procedure:
Part A: 2,2'-dihydroxy-5,5'-dimethyoxy-1,1'-biphenyl was prepared by the dealkylation of 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethyoxy-1,1'-biphenyl using a procedure described by Tashiro, M.; Fukata, G., and Yamato, T.; Organic Preparations and Procedures Int., 8, 263 (1976). AlCl3 (10 g) and 10 g of 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl were mixed in 125 ml of benzene and heated at 40° C. for 3 h. The mixture was cooled in ice and 125 ml of 10% HCl solution was added slowly. The organic layer was separated and washed with 3×125 ml of 10% NaOH. The basic solution was neutralized with concentrated HCl and extracted with 3×100 ml of ether. The ether layer was dried over Na2SO4. After filtering and removing the solvent by vacuum evaporation, the brown oil was washed with hexane and then the product crystallized from CH2Cl2 /hexane. 2.202 g of 2,2'-dihydroxyl-5,5'-dimethoxy-1,1'-biphenyl was obtained as a white solid. 1H nmr (300 MHz, CD2Cl2): 6.9-6.8 (m, 6H), 5.71 (s, 2H), 3.78 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2ccc(F)cc2)C(C)C)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)COc2ccc(F)cc2)C(C)C)n(C)c2ccccc12
Yield: 64.3 %

Procedure:
Treatment of the product of Example 84 (72 mg, 0.118 mmol) with TFA as described in Example 80 gave the titled product (42.0 mg, 68%) as a pale yellow powder. MS C30H36FN3O6, [M+Na]+ =576, [M−H]− =552. TLC (hexane/EtOAc, 50/50): Rf=0.33.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[C:24]([O-])(=[O:26])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]1[CH:18]=[CH:19][C:20]([CH:24]=[O:26])=[CH:21][CH:22]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCCCCCN(C)c1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCCN(C)c1ccc(C=O)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Phosphorous oxychloride (145 g, 0.95 mol) was added dropwise at 5° C. to 280 mL of stirred N,N-dimethylformamide (DMF), and the mixture was stirred at 5° C. for 2 hours. N-(6-Acetoxyhexyl)-N-methylaniline (Example 2, 230 g, 0.93 mol) was added slowly, and the reaction mixture was heated at 90° C. for 3 hours. After cooling, the solution was poured onto 500 g of ice and the resulting mixture was neutralized to pH 5 with sodium acetate. The mixture was extracted with dichloromethane (4×200 mL), the combined extracts were dried (MgSO4), and the solvent was removed at reduced pressure. The brown residue was distilled in vacuo to provide 186 g (73%) of a yellow oil, bp 195° C. (0.15 mm).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>COCCCOCCCO>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CCOC(=O)C1CCNCC1
Agent: COCCCOCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2cc(C)ccn2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
2-Bromo-4-methylpyridine (860 mg, 5 mmol), ethyl piperidine-4-carboxylate (865 mg, 5.5 mmol) and DIPEA (958 μl, 5.5 mmol) were mixed in dipropyleneglycolmonomethylether (10 ml) and stirred at 150° C. overnight. Additional ethyl piperidine-4-carboxylate (865 mg, 5.5 mmol) was added and stirring was continued at 150° C. for 24 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient from 0 to 30% ethyl acetate in DCM) to give 700 mg of a brown solid (2.8 mmol, 56%) MS (multi-mode) m/z=249.1 [M+1]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15]([NH:17][CH3:18])=[O:16])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:18][NH:17][C:15]([NH:14][CH:11]([CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1)[CH2:12][CH3:13])=[O:16]
Reactant: CCC(NC(=O)NC)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(NC(=O)NC)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-(1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)-3-methylurea (as prepared in the previous step, 48 mg, 0.19 mmol, 1.00 equiv) in CH3CN (2 mL), hydrogen chloride (aq, 2M) (2 mL). The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 8 with potassium carbonate (1 mol/L). The resulting solution was extracted with 3×10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.[OH:27][NH:28]/[C:29](=[N:38]\[H])/[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.[O-]CC.[Na+]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:27][N:28]=[C:29]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[N:38]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: [H]/N=C(/Cc1ccc(O)cc1)NO
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(O)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 17.6 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (29 mg, 0.078 mmol) and (1Z)—N-hydroxy-2-(4-hydroxyphenyl)ethanimidamide (14 mg, 0.084 mmol) were heated in EtOH (1 ml) with 21% ethanolic sodium ethoxide (0.043 ml, 0.117 mmol) under microwave irradiation at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated. This material was stirred with EtOH (1 ml) and 2M NaOH (0.5 ml) for 18 h, before being worked up again by partition between EtOAc and 2M HCl. Purification by MDAP afforded the title compound (6.5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CNC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)COc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide [Example 3a)] with 1-bromomethyl-3-fluoro-benzene in 2-butanone using potassium carbonate as the base yielded the 2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=290 (M+H)+.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]=[C:11]([C:15]2[CH:30]=[CH:29][C:18]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:10]1)C1C=CC=CC=1>[Pd].CO>[ClH:1].[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)=[CH:29][CH:30]=2)[CH2:10]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3=CCCN(Cc4ccccc4)C3)cc2)nc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reaction time: 3.5 h
Yield: 38.7 %

Procedure:
Combine the product of example 321 (0.0421 g, 0.0998 mmol), 10% Pd—C (2 spatula tips), and methanol (2.0 mL). Bubble one balloon of hydrogen gas through solution then stir under ca. 1 atm. After 3.5 h, filter the reaction mixture through Celite®, concentrate, and purify by reverse-phase HPLC to provide 0.0129 g (39%) of the title compound as a white solid: mass spectrum (electrospray): m/z=298.1 (M+1); 1H NMR (methanol-d4): 8.86 (s br, 1H), 8.59 (dd, 1H, J=2.0, 8.8 Hz), 7.53 (d, 2H, J=8.3 Hz), 7.32 (d, 2H, J=7.8 Hz), 7.19 (d, 1H, J=8.8 Hz), 3.51 (d, 1H, J=8.3 Hz), 3.25-3.08 (m, 3H), 2.18-2.08 (m, 2H), 2.06-1.84 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>[Pt].C(#N)C.C1(C)C=CC=CC=1>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A glass Parr vessel was charged with 5% platinum on carbon catalyst (5 g), 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (57 g, 0.17 mol), and a 1:1 solution of acetonitrile/toluene (1800 mL). The vessel was evacuated, charged with hydrogen gas (50 psi, 3.4×105 Pa), and shaken for 5 hours. The reaction mixture was then filtered through a 0.2 micron polytetrafluoroethylene (PTFE) membrane filter. The filtrate was concentrated to provide 49 g of 1-[(3-amino-7-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol as a bright yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(Oc3ccccc3)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(Oc3ccccc3)cc2)S(C)(=O)=O)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-{3-[(4-phenoxy-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 7.14 (m, 4H), 6.97 (m, 4H), 4.31 (s, 2H), 4.30 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.78 (s, 3H), 2.61 (t, 2H).