Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([P:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)=[N:2]1.[H-].[Na+].[H][H].[CH2:29](Br)[CH:30]=[CH2:31]>C1COCC1>[CH2:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([P:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:9]=[CH:10][CH:11]=2)=[N:2]1)[CH:30]=[CH2:29]
Reactant: [H][H]
Reactant: c1ccc(P(c2ccccc2)c2cccc(-c3cc[nH]n3)c2)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1ccc(-c2cccc(P(c3ccccc3)c3ccccc3)c2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
25 mmol of 5 are dissolved in 50 ml of THF and mixed with 25 mmol of NaH. After the termination of the evolution of hydrogen, 25 mmol of allyl bromide are added and the mixture is refluxed for 4 h. After cooling to room temperature, it is filtered off from the NaBr precipitation and the solvent is removed in a vacuum. A colorless oil remains. Yield: 98%. 1H NMR (400.1 MHz, 25° C., DMSO-d6): δ 7.80-7.25 (m, 14H, ar H, 5pz-H), 7.06 (t, 1H, 3JHH=6.6 Hz, 5-H), 6.63 (d, 1H, 3JHH=2.4 Hz, 4pz-H), 6.07-5.96 (m, 1H, —CH═CH2), 5.20-5.11 (m, 2H, —CH═CH2), 4.75 (d, 2H, 3JHH=5.7 Hz, —CH2CH═). 13C{1H} NMR (100.6 MHz, 25° C., DMSO-d6): δ 150.5 (C-3pz), 139.4 (C-5pz), 137.6 (d, 1JPC=12.0 Hz, C-1), 134.7 (—CH═CH2), 134.1 (d, 2JPC=19.4 Hz, C-o), 132.9 (d, 3JPC=2.8 Hz, C-3), 132.8 (d, 2JPC=14.8 Hz, C-6), 132.4 (d, 1JPC=9.2 Hz, C-1), 130.9 (d, 2JPC=25.0 Hz, C-2), 130.0 (d, 3JPC=4.6 Hz, C-5), 129.8 (s, C-p), 129.6 (d, 3JPC=6.5 Hz, C-m), 126.7 (s, C-4), 118.7 (—CH═CH2), 103.6 (C-4pz) 54.7 (—CH2CH═). 31P{1H} NMR (162.0 MHz, 25° C., DMSO-d6): δ 4.90.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.Cl.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH:28][C:15]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]3([CH3:14])[CH2:11][O:12][CH2:13]3)[N:6]=2)=[O:17])[CH2:27][O:26][CH2:25]1
Reactant: NC1(c2nccs2)COC1
Reactant: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Agent: Cl
Product: CC1(COc2nc(C(=O)NC3(c4nccs4)COC3)ccc2Br)COC1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=440.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]([CH3:20])[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])=[CH:15][CH:16]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)s1
Product: CN(CCc1ccc(F)cc1)C(=O)c1ccc(Br)s1

Procedure:
From 5-bromo-thiophene-2-carboxylic acid (1.0 g) and [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (740 mg), a colorless solid (1.39 g) was obtained, in the same way as Preparation Example 118-b).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][C:15]2[N:16]([C:18]([C:21]3([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:17]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1COCC1.CO.O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][C:15]2[N:16]([C:18]([C:21]3([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate (100 mg, 0.2 mmol) in 5 ml of THF-MeOH—H2O (3:1:1) was added 2M of lithium hydroxide in water (0.23 mL) at 0° C. under N2. The solution was stirred for 10 min at 0° C., and 1.5 h at RT. The reaction solution was concentrated to dryness to give the desired product which was directly used in next step without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([C:29]3[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=3)=[O:5])=[CH:22][C:10]=2[CH:11]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: CSc1ccc([Mg]Br)cc1
Product: CSc1ccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)cc1

Procedure:
The product from Example 71E and 4-(methylthio)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.45 (d, 3H), 1.75 (m, 1H), 1.80 (m, 2H), 2.30 (m, 2H), 2.38 (m, 1H), 2.54 (s, 3H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.4 (dd, 2H), 7.7 (bs, 1H), 7.6 (dd, 1H), 7.75 (m, 3H), 8.0 (d, 1H); MS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:21][C:22]([C:24]1[CH:35]=[C:34]([CH3:36])[C:27]2[N:28]=[C:29]([CH2:31][CH2:32][CH3:33])[NH:30][C:26]=2[CH:25]=1)=[O:23])[CH2:9][C:10](=[O:20])[NH:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[N:57](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:56]=[N:55][N:54]=2)=[CH:43][CH:42]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([C@@H:8]([NH:21][C:22]([C:24]1[CH:35]=[C:34]([CH3:36])[C:27]2[N:28]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[C:53]4[NH:54][N:55]=[N:56][N:57]=4)=[CH:43][CH:42]=3)[C:29]([CH2:31][CH2:32][CH3:33])=[N:30][C:26]=2[CH:25]=1)=[O:23])[CH2:9][C:10](=[O:20])[NH:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2c(C)cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
To a cold solution of 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid ((R)-1-benzyl-2-benzyloxycarbamoylethyl)amide (800 mg, 825 μmol) in DMF (50 mL) in ice bath was added NaH (60% dispersion in oil; 99 mg, 2.5 mmol) in small portions. After stirring for 30 minutes at the same temperature, 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole (460 mg, 825 μmol) was added to the mixture, and the final mixture was stirred at room temperature for 12 hours, then at 70° C. for 6 hours. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaCl. The organic layer was dried over MgSO4, and evaporated in vacuo, affording a pale yellow oil. The oil was dissolved in DCM (10 mL), followed by the addition of TFA (10 mL). The final mixture was stirred at room temperature for 1 hour, and concentrated to dryness, yielding a pale yellow oil. The oil was rinsed with ether and dried. The crude material was found to contain two regioisomeric N-alkylation products, compound 5a (a major product) and compound 5b (a minor desired product). ESMS [M+H]+ calcd for C43H42N8O3, 719.35. found 719.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O>[N:12]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Brc1cncc2cccnc12
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(N3CCNCC3)cncc2c1
Temperature: 120 °C
Yield: 35.4 %

Procedure:
To an oven-dried 100 mL flask under a nitrogen atmosphere was added 8-bromo-[1,6]-naphthyridine (1.3 g, 6.2 mmol), piperazine (3.21 g, 37.3 mmol), and sodium t-butoxide (900 mg, 9.33 mmol). The solids were suspended in anhydrous o-xylenes (40 mL), and Pd(dba) (285 mg, 5 mol %) and P(t-Bu)3 (0.31 mL, 1.24 mmol) were added. The reaction mixture was heated at 120° C. for 3 hours. The cooled reaction mixture was poured into H2O (100 mL) and extracted into EtOAc (1×100 mL) and CH2Cl2 (2×100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, and the resulting oil was chromatographed (10% MeOH/CH2CH2+NH4OH) affording 470 mg (35%) of the title compound as a dark gold oil. An analytical sample was prepared as the HCl salt from EtOAc giving a brown solid: mp decomposes above 200° C. MS(+)APCI m/z 215 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1
Temperature: 100 °C

Procedure:
A stirred mixture of benzyl 4-(aminomethyl)-piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (10.0 g, 0.040 mol), 2-chloro-5-fluoropyrimidine (5.3 g, 0.040 mol) and cesium carbonate (26.2 g, 0.081 mol) in DMF (100 mL) was heated at 100° C. for 2 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (400 mL), washed with aqueous saturated NaHCO3 (100 mL), water (5×100 mL), and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (0.5 kg), eluting with 50–100% ethyl acetate in hexane to give the title compound. M.S. (M+1): 345.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([O:25]C)[N:15]3[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:11]([NH2:27])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:27][C:11]1[N:10]=[C:9]([O:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:17]=[C:16]2[C:12]=1[NH:13][C:14](=[O:25])[N:15]2[CH2:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1nc(OCC2CCCCC2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (RS105369-181A2) (0.1657 g) was dissolved in methanol (5 mL) and then added 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then evaporated under reduced pressure to give a solid that was then suspended in water (1 mL) and methanol (˜2-3 mL) before being neutralised (to pH 7) by the addition of 2N sodium hydroxide. The resultant mixture was evaporated to near dryness before being suspended in water (3 mL) and the solid is filtered off under suction. This solid was then washed with a few drops of methanol and then air-dried under suction before finally being dried to constant weight under vacuo at 50° C. This gave the title compound as a white solid (134 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[N:16]=2)C=O)=[CH:4][CH:3]=1.C1(P(=[CH:49][CH:50]=[O:51])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:52]1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[N:16]=2)[CH:52]=[CH:49][CH:50]=[O:51])=[CH:4][CH:3]=1
Reactant: COCCOCn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Product: COCCOCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenal (1.4 g, 3.5 mmoles) and triphenylphosphoranylideneacetaldehyde (1.3 g, 4.3 mmoles) [isolated in Example 69, Step A] in 25 mL of benzene was heated at reflux temperature for 12 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with 20% (v/v) ethyl acetate in hexane to give 0.9 g of the title compound as an oil. MS (CI): m/e=427 for (M+H)+ ;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([I:11])=[C:6]([NH2:12])[CH:5]=1.[CH2:14](I)[CH3:15].CC(C)([O-])C.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH3:15])[C:7]([I:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: CCI
Reactant: COC(=O)c1cc(N)c(I)c(O)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(N)c1I
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-amino-5-hydroxy-4-iodo-benzoic acid methyl ester (0.25 g, 0.85 mmol, 1.0 equiv) in DMF (3 mL) and ethyl iodide (0.10 mL, 0.146 g, 0.94 mmol, 1.1 equiv) at 0° C. was added sodium tert-butoxide (0.11 g, 0.94 mmol, 1.1 equiv) in small portions over a time period of 10 min. After stirring for 1 h, the cooling bath was removed and the the reaction mixture stirred at rt for an additional 18 h. The solution was concentrated by evaporation under reduced pressure and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (2:1) yielding 0.19 g (69%) of the title compound. 1H NMR (250 MHz, CDCl3): δ 1.49 (t, J=7.0 Hz, 3H), 3.89 (s, 3H), 4.11 (q, J=7.0 Hz, 2H), 4.33 (br s, 2H), 6.82 (d, J=2.7 Hz, 1H), 7.07 (d, J=2.7 Hz, 1H). MS (EI): 321.0 [M]+.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH3:10][N:8]([CH3:9])[C:6]([C:5]1[CH:11]=[C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:13]=[CH:14][C:4]=1[NH:1][C:2]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:3])=[O:7]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Reactant: C1COCCN1
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Yield: 24.5 %

Procedure:
Into a 3 mL reaction vial were added 2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (48 mg, 0.085 mmol), methylene chloride (1 mL) and morpholine (40 μL, 0.455 mmol, pre-treated with molecular sieves). The solution was stirred at room temperature for at least 12 h and monitored by HPLC. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 100 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuum. Purification by Mass-triggered HPLC (formic acid ACN/H2O gradient) followed by lyophilization provided 10.4 mg of the title compound as a white powder. 1H-NMR (500 MHz, d6-DMSO) δ 11.91 (br.s, 1H), 8.73 (br.s., 1H), 8.52 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.71 (m, 3H), 7.80 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.28 (app t, J=7.5 Hz, 1H), 7.11 (d, J=7 Hz, 1H), 7.03 (t, J=7 Hz, 1H), 3.80 (s, 3H), 3.60 (m, 4H), 3.51 (m, 4H), 2.96 (br s, 6H); MS: m/z 500.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1.Cl.C(OC(N1CC[C@@H](CN)C1)=O)(C)(C)C.ClC1OC2C([F:43])=CC=CC=2N=1>O1CCOCC1>[ClH:1].[F:43][C:3]1[C:4]2[O:8][C:7]([NH:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)=[N:6][C:5]=2[CH:16]=[CH:17][CH:2]=1
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Reactant: Fc1cccc2nc(Cl)oc12
Agent: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc2nc(NC[C@@H]3CCNC3)oc12

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride (example 1, step 2) the title compound was prepared from (S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloro-7-fluoro-benzooxazole (Bioorganic & Medicinal Chemistry Letters 2007, 17, 4689) and subsequent cleavage of the tert-butyloxy carbonyl-protecting group through treatment with HCl in dioxane. MS (m/e): 236.1 (MH+).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+:7].[Na+].[C:9]([NH:13][NH:14][C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])(=[O:12])[CH:10]=[CH2:11]>O>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+:7].[C:9]([NH:13][NH:14][C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])(=[O:12])[CH:10]=[CH2:11].[Na+:7]
Reactant: C=CC(=O)O
Agent: C=CC(=O)NNc1ccc(C(=O)[O-])c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
A mixture of acrylic acid (80.9 g) and deionized water (114 g) in a 500 mL beaker equipped with a magnetic stirrer is cooled to 7–10° C. and a 50% solution of sodium hydroxide in water (92 g) is added dropwise over 30 minutes while maintaining the reaction mixture temperature below 15° C. After the addition of sodium hydroxide, powdered N-acryloyl-4-amino salicylic acid (19 g, prepared as described in Example 11) is added and the mixture is stirred to form a homogenous solution.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[Cl:12]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C>[Cl:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1c(Cl)ccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A suspension of 3.0 g of 4-methyl-2-oxindole was stirred in 50 mL of acetonitrile at room temperature while 3.3 g of N-chlorosuccinimide was added in portions. Trifluoroacetic acid (1 mL) was then added. The suspension was stirred at room temperature for 3 days during which time solid was always present. The white solid was collected by vacuum filtration, washed with a small amount of cold acetone and dried overnight in a vacuum oven at 40° C. to give 2.5 g (68%) of 5-chloro-4-methyl-2-oxindole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH:20]=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH2:23]([NH2:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][NH:25][CH2:23][CH3:24])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (5-chloro-4′-fluoro-2′-formyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][CH:29]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: O=CCCCc1c[nH]c2ccc(F)cc12
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCCCCc1c[nH]c2ccc(F)cc12)CO3
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 4-(5-fluoro-1H-indol-3-yl)butanal (21), 63 mg, 0.294 mmol) in acetic acid (37 μl, 0.62 mmol) and methanol (4 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. Resulting mixture was stirred for 1.5 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with 60% EtOAc/Hexane to give (25) as a solid (90 mg, 78%). MS (ES) m/z 394.2;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[C:5]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2-c2ccc(CC(C)C)cc2)c1C
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)cc2-c2ccc(CC(C)C)cc2)c1C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of the compound of Example 43 (0.4 g, 1.0 mmol) and pyridine (0.082 mL, 1.0 mmol) in acetone (3 mL) was added benzoyl chloride (0.12 mL, 1.0 mmol). The mixture was stirred for 18 hours and concentrated. The residue was dissolved in methanol (50 mL) and a 5% solution of sodium hydrogen carbonate in water (10 mL) was added. The solution was stirred for 1 hour and the methanol was removed under vacuum. The aqueous residue was acidified to pH 3 with 6N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, and dried (magnesium sulfate). The residue was chromatographed on silica with (1:1) ethyl acetate:hexanes to afford 98 mg (19%) of the title compound as a tan solid, mp 207-211° C.
Reaction SMILES: [O:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[C:2]1=2>C(Cl)Cl.CCCCCC>[O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[C:2]1=2
Reactant: CCOC(=O)c1cc2ccc3ccc4ccccc4c3c2o1
Solvent: ClCCl
Solvent: CCCCCC
Product: OCc1cc2ccc3ccc4ccccc4c3c2o1
Yield: 91 %

Procedure:
Using the procedure outlined in Example 14A, ethyl phenanthro[4,3-b]-furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 91% yield of phenanthro[4,3-b]furan-2-methanol, mp 125°-126°, (C,H), (CH2Cl2 /hexane).