Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15]4[CH2:21][CH:22]5[NH:26][CH:25]([C:14]=4[C:13]=3[C:12]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[CH2:21][CH:22]4[NH:26][CH:25]([C:14]3=2)[CH2:24][CH2:23]4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(Cl)cc4)ccc31)C1CCC(C2)N1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc(Cl)cc4)ccc31)C1CCC(C2)N1
Yield: 26 %

Procedure:
The product of step A was subjected to Boc-deprotection with TFA following the procedure of Example 28, Step B. The crude product was purified by flash column chromatography (SiO2, 1:9 methanol/dichloromethane) to give 2-(4-chlorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (20 mg, 26%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.12-8.14 (m, 1H), 7.83-7.94 (m, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.51-7.55 (m, 2H), 7.45-7.48 (m, 1H), 4.59 (d, J=2.7 Hz, 1H), 4.01-4.05 (m, 1H), 3.64 (s, 3H), 3.16-3.23 (m, 1H), 2.61-2.67 (m, 1H), 1.94-2.23 (m, 3H), 1.59-1.67 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH3:21])[CH:10]=[N:11][C:12]=2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH3:21])[CH:10]=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 5-phenyl-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (110 mg, 0.36 mmol) in benzene (2.0 mL) were added sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and phenylboronic acid (53 mg, 0.43 mmol). The reaction mixture was refluxed overnight, and then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (74 mg, 67%). MS (CI/NH3) m/z 303 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.65-2.10 (m, 4H), 2.27-2.38 (m, 1H), 2.49 (s, 3H), 2.63-2.72 (m, 1H), 3.08-3.16 (m, 1H), 3.93-4.05 (m, 2H), 7.24 (d, J=3.0 HZ, 1H), 7.44-7.48 (m, 5H), 8.09 (d, J=3.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](Br)=[C:13]([N+:18]([O-])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc([N+](=O)[O-])c(Br)cc2C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Yield: 100.7 %

Procedure:
A total of 59 g (0.16 mol) of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 10 g of 5% palladium on calcium carbonate and 49 g of ammonium acetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for 5 hrs. The reaction was filtered, concentrated, basified to pH 12 with 4N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to yield 40 g of the title compound in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[O:26][C:25]3([CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]3)[C:18]3([N:22]=[C:21]([NH2:23])[C:20]([CH3:24])=[N:19]3)[C:16]=2[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[O:26][C:25]4([CH2:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][CH2:31]4)[C:18]4([N:22]=[C:21]([NH2:23])[C:20]([CH3:24])=[N:19]4)[C:16]=3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(N)=N1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Oc1ccc(-c3cccc(Cl)c3)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 47 %

Procedure:
3-Chlorophenylboronic acid (47.7 mg, 0.31 mmol), 5′-bromo-4-methoxy-5″-methyldispiro-[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine (Example 29, 77 mg, 0.20 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (8.37 mg, 10.18 μmol) were put in a microwave vial and dissolved in dry dioxane (2 mL). A 2 M aq. solution of K2CO3 (0.204 mL, 0.41 mmol) was added, the mixture was degassed with nitrogen gas and the mixture was heated at 120° C. for 20 min in a microwave reactor. The mixture was combined with a second reaction from 10 mg (0.03 mmol) of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine and concentrated. EtOAc (7 mL) and a sat. aq. solution of NaHCO3 (5 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (5 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by preparative chromatography, yielding 38.5 mg of the title compound (41% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.21 (m, 1H), 1.46 (m, 3H), 1.82 (m, 2H), 1.98 (m, 2H), 2.21 (s, 3H), 3.09 (m, 1H), 3.22 (s, 3H), 6.71 (br. s., 2H), 6.85 (d, 1H), 6.98 (d, 1H), 7.32 (m, 1H), 7.40 (s, 1H), 7.47 (m, 1H), 7.51 (m, 1H), 7.54 (s, 1H); MS (APCI+) m/z 410 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:25][N:24]=3)=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:39][C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:41]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[N:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:34][CH2:33][N:32]([CH:40]([CH3:41])[CH3:39])[CH2:31]4)=[CH:25][N:24]=3)=[CH:19][CH:20]=2)[CH3:14])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN(C(=O)Nc1cc(C(C)(C)C)on1)c1ccc(NC(=O)c2ccc(OC3CCNC3)cn2)cc1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(N(C)C(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 68 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)-1-methylureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (45 mg, 68%) was prepared using a procedure analogous to that described in Example 20, substituting N-(4-(3-(5-tert-butylisoxazol-3-yl)-1-methylureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from the Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[F:33]>>[F:33][C:18]1[CH:19]=[C:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH:21]=[CH:22][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)c(F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]([F:16])([F:15])[F:14])[CH:7]=1.[H-].[Na+].[CH3:20][OH:21]>>[Br:1][C:2]1[C:3]([O:21][CH3:20])=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]([F:16])([F:15])[F:14])[CH:7]=1
Reactant: FC(F)(F)c1nccn1-c1cnc(Cl)c(Br)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1ncc(-n2ccnc2C(F)(F)F)cc1Br
Yield: 80 %

Procedure:
3-Bromo-2-chloro-5-(2-trifluoromethylimidazol-1-yl)pyridine (318 mg, 0.97 mmol) in methanol (12 ml) was treated with sodium hydride (54 mg, 60% dispersion in oil, 1.41 mmol) and refluxed for 3 hrs. After cooling and concentration, the residue was purified by silica chromatography, to give the product as a yellow solid (252 mg, 80% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13]C(C)(C)[NH:11][C:10](=[O:16])[C:9]=2[CH:17]=1.[ClH:18]>C(N)C1C=CC=CC=1>[ClH:18].[CH2:10]([NH:11][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[C:9]([C:10]([NH2:11])=[O:16])[C:8]([OH:13])=[CH:7][CH:6]=1)[C:9]1[CH:17]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1
Agent: Cl
Solvent: NCc1ccccc1
Product: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reaction time: 0.5 h

Procedure:
A suspension of 60 g of 6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one in 110 ml of benzylamine is heated, with stirring, for 30 minutes in a bath at 80°. The reaction mixture is thereupon adjusted with conc. hydrochloric acid, using ice-cooling, to a pH value of about 3, and is allowed to stand until crystallisation occurs. The crystals are filtered off with suction after 4 hours, washed with 100 ml each of water and of ethyl acetate, and dried. The crude 5-(2-benzylamino-ethoxy)-salicylamide hydrochloride obtained melts at 214°-216°. The base liberated therefrom melts at 107°-108° (from ethyl acetate/ether).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].FC(F)(F)C(O)=O.[O:72]=[C:73]1[CH:77]=[CH:76][C:75](=[O:78])[N:74]1[CH2:79][CH2:80][C:81]([CH3:87])([CH3:86])[C:82]([NH:84][NH2:85])=[O:83]>>[O:78]=[C:75]1[CH:76]=[CH:77][C:73](=[O:72])[N:74]1[CH2:79][CH2:80][C:81]([CH3:87])([CH3:86])[C:82]([NH:84][NH:85][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:83]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: CC(C)(CCN1C(=O)C=CC1=O)C(=O)NN
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)C(C)(C)CCN1C(=O)C=CC1=O)C(C)C

Procedure:
6 mg (6.7 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 61) were reacted with 3 mg (8.7 μmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2,2-dimethylbutanehydrazide trifluoroacetate in analogy to Intermediate 142 to give 2 mg (27% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
7.5 g of the 4-dodecylphenol obtained in (1) above was dissolved in 25 ml of acetic acid and 12.6 ml of 30% aqueous nitric acid solution was dropwise added slowly to the resulting solution, and then the resulting mixture was subjected to reaction at about 10° C. for one hour. The reaction mixture was added to 35 g of ice water and the extraction with 35 ml of diethyl ether was conducted three times. The diethyl ether layer thus obtained was washed with 35 ml of 5% aqueous NaHCO3 solution, and then dried with MgSO4. Subsequently, the solvent was distilled off to obtain 5.93 g of 4-dodecyl-2-nitrophenol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][C:5]=2[CH3:16].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:34][C@H:33]2[NH:35][CH2:36][C@@H:28]1[CH2:29][CH:30]=[CH:31][CH2:32]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:35]1[CH2:36][CH:28]3[N:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:34][CH:33]1[CH2:32][CH:31]=[CH:30][CH2:29]3)[CH:7]=[CH:6][C:5]=2[CH3:16]
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: Cc1cc2c(OCC3CO3)ccc(C)c2[nH]1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(OCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)ccc(C)c2[nH]1

Procedure:
2,7-Dimethyl-4-oxiranylmethoxy-1H-indole (30 mg, 0.138 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (40 mg, 0.15 mmol), DIPEA (0.1 mL, 0.55 mmol), ethanol (2 mL) were heated for 900 sec. at 120° C. in a μW reaction tube to yield crude product. The solvent was evaporated under reduced pressure to yield a solid that was purified with flash chromatography gradient [0% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: [B:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][O:2]1.[CH2:18]([N:20](CC)[CH2:21]C)C.CS(Cl)(=O)=O.CNC>ClCCl.O>[B:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][N:20]([CH3:21])[CH3:18])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1B1OCc2ccccc21
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1ccccc1B1OCc2ccccc21
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of (2-(benzo[c][1,2]oxaborol-1(3H)-yl)phenyl)methanol (300 mg, 1.34 mmol) in dichloromethane (10 mL) were added sequentially triethylamine (0.373 mL, 2.7 mmol) and methanesulfonyl chloride (0.125 mL, 1.60 mmol) at 0° C. After stirring for 30 min, dimethylamine (2M in tetrahydrofuran; 3 mL) was added, and the mixture was sirred for another 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (1:2 hexane/ethyl acetate) followed by recrystallization from diisopropyl ether/hexane to give the title compound (185 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.41 (s, 3H), 4.09 (br d, J=8.5 Hz, 2H), 4.87 (d, J=13.2 Hz, 1H), 5.05 (d, J=13.2 Hz, 1H), 7.0-7.3 (m, 8H); ESI-MS m/z 252 (positive); C16H18BNO=251
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c8) the title compound is obtained as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])N(CCO)N=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[N:9]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: Cc1ccccc1NN
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccccc3C)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C (see starting compounds) and 2-methylphenylhydrazine as described for compound 35. Crystallization from methanol. M.p. 144°-145° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:24]([OH:32])=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[C:24]([OH:32])=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[OH:21])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1cccc(F)c1O
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cccc(F)c4O)n3)n2)c(O)c1
Yield: 17 %

Procedure:
6-(3-Fluoro-2-hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 3-fluoro-2-hydroxyphenylboronic acid in 17% yield using method F; δH [2H6]-DMSO 13.37,(1H, b), 8.38,(1H, d), 8.34-8.15,(4H, m), 8.10,(1H, d), 8.01,(1H, d), 7.95,(1H, d), 7.34,(1H, t), 6.98,(1H, m), 6.81,(2H, m), 2.33,(3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH3:11][S:12][C:13]1[N:17]([CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:16]2[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=2[N:14]=1.N1CC(=O)NC1=O.C(O)(C(F)(F)F)=O>>[CH3:10][C:3]1([CH2:2][NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH2:18][N:17]3[C:16]4[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=4[N:14]=[C:13]3[S:12][CH3:11])=[CH:20][CH:21]=2)[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7]1
Reactant: CC1(CN)NC(=O)NC1=O
Reactant: CSc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Agent: O=C1CNC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccccc2n1Cc1ccc(C(=O)NCC2(C)NC(=O)NC2=O)cc1
Yield: 38.1 %

Procedure:
5-(aminomethyl)-5-methylhydantoin (109a)(55 mg, 0.31 mmol) was coupled with 4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoic acid (108 mg, 0.37 mmol) using general coupling method B to give 50 mg (39%) of the product hydantoin as a TFA salt. MS found: (M+H)+=425.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].N1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:28](=[O:29])[O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3ccc(NC(=O)Oc4ccccc4)cc23)c1
Yield: 95 %

Procedure:
To a solution of N4-(3-ethynylphenyl)quinazoline-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 mL) containing pyridine (37 μL, 0.46 mmol) was added phenyl chloroformate (49 μL, 0.38 mmol) dropwise at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The combined organic layers were concentrated to give phenyl 4-(3-ethynylphenylamino)quinazolin-6-ylcarbamate as a yellow solid in 95% yield and used in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1>[CH3:13][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of 6-nitro-1H-indole (100 mg, 0.62 mmol) and 18-Crown-6 (180 mg, 0.68 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was slowly added potassium tert-butoxide (76 mg, 0.68 mmol) followed by methyl iodide (42 μL, 0.68 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 91 mg (84%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[C:28]([NH:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1)=[O:34])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Product: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Temperature: 180 °C

Procedure:
A mixture of the title D compound, 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluoro-benzenesulfonyl)phenol (0.64 g, 1.65 mmol) and 2 mL of diethyl oxalate is heated at 180° C. for 3 h. The reaction is cooled to RT and diethyl oxalate is removed under vacuum. Chromatography on silica (eluant; EtOAc/hexane —1/3→2/3) affords N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester: NMR (CDCl3) 1.46 (t, 3H, J=7.5), 2.06 (s, 6H), 4.42 (q, 2H, J=7.5), 6.90-6.98 (m, 3H), 7.22 (app t, 2H, J=8.3),7.40 (s, 2H), 7.87-7.93 (m, 2H), 8.87 (br s, 1H); ESI-MS 486 [M-1]−.