Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([N:29]([CH3:42])[C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@@H:30]([N:29]([CH3:42])[C:27](=[O:28])[O:26][C:23]([CH3:22])([CH3:25])[CH3:24])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:36][CH:37]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 77.3 %

Procedure:
Preparation of example 151 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (2R)-2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (57 mg, 0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (14 mg, 0.047 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (18 mg, 0.047 mmol) were added after 24 hours to drive the reaction to completion. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (55 mg, 0.099 mmol) as a yellow powder in 78% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.[Br:11][C:12]1[N:13]=[C:14](Br)[C:15]2[N:16]([CH:18]=[CH:19][N:20]=2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:14]3[C:15]4[N:16]([CH:18]=[CH:19][N:20]=4)[CH:17]=[C:12]([Br:11])[N:13]=3)[CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: Nc1ccc2cnoc2c1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cn2ccnc2c(Nc2ccc3cnoc3c2)n1

Procedure:
A quantity of 0.13 g (1 mmole) of Benzo[d]isoxazol-6-ylamine is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford Benzo[d]isoxazol-6-yl-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.O.[C:11](=[O:14])([O-])[O-:12].[K+].[K+]>C1COCC1>[C:3]([O:12][C:11]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:14])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCCNC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of nipecotic acid, 2.0 g (16.0 mmol) in 20 mL of THF and 20 mL of water was added 4.7 g (33.6 mmol) of potassium carbonate and 3.5 g (16.0 mmol) of Boc-anhydride. The resulting solution was stirred overnight at ambient temperature then concentrated to dryness. The residue was dissolved in water, washed with ether and acidified to pH=2 with 5N HCl. The acidic aqueous layer was extracted with 20% isopropanol/chloroform. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to yield 3.2 g (86%) of the desired mixture of isomers as a white solid. MS (ion spray) 228.2 (M−1).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]2[C:10](=[C:11]([O:16]C)[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:18])[CH:7]=1.C([SiH](C(C)C)C(C)C)(C)C>C(Cl)Cl>[Br:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:18])[CH:7]=1
Reactant: COc1cccc2c(Br)cc(C)nc12
Agent: BrB(Br)Br
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Br)c2cccc(O)c2n1
Temperature: 25 °C

Procedure:
BBr3 (1 M in DCM, 108 mL, 108 mmol) was added dropwise to a stirred solution of 4-bromo-8-methoxy-2-methyl-quinoline (7.8 g, 31 mmol) and triisopropyl-silane (6.2 mL, 31 mmol) in anhydrous DCM (300 mL) at −80° C. The reaction mixture was allowed to warm to room temperature over 4 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between DCM (300 mL), water (50 mL), and concentrated aqueous NH3 (20 mL). The aqueous layer was extracted with DCM (2×300 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/EA 10:1) to give the title compound. MS (m/z): 238.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.Cl.[C:15]([OH:21])(=O)[CH2:16][CH2:17][CH2:18][CH3:19].[NH4+].[OH-]>O.[Ni].CO.C1COCC1>[CH2:5]([C:4]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[C:5]([NH:11][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=2)[CH2:6][CH2:7][CH3:2]
Reactant: CCCCC(=O)O
Reactant: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCC(=O)Nc1cnc2nc(CCCC)[nH]c2c1
Temperature: 95 °C

Procedure:
A mixture of 2-amino-3,5-dinitropyridine (5.32 g, 28.9 mmol), THF (100 mL), methanol (250 mL) and Raney-nickel (3 mL of a 1:1 suspension in H2O) was stirred under H2 (1 atm.) was stirred for 5 h. The reaction mixture was quickly filtered into a receiving flask containing 5 mL of conc. HCl and the solvent was removed in vacuo at r. t. To this crude 2,3,5-triaminopyridine.HCl was added valeric acid (9.43 mL, 86.7 mmol) and polyphosphoric acid (100 mL) and this mixture was heated to 95° C. for 6 h. The warmed mixture was poured into stirred ice-H2O (200 mL) and this mixture was cooled and neutralized (to pH 4) by the addition of conc. NH4OH. Extraction with EtOAc(3×75 mL), concentration, and purification (SiO2, 5% MeOH/EtOAc) gave the title compound as solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][O:50][CH2:51][C:52]1([NH2:56])[CH2:55][CH2:54][CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][C:52]4([CH2:51][O:50][CH3:49])[CH2:55][CH2:54][CH2:53]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCC1(N)CCC1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CCC1
Temperature: 70 °C
Yield: 39.5 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (48 mg, 0.157 mmol), HATU (119 mg, 0.313 mmol) and 1-(methoxymethyl)cyclobutanamine hydrochloride (47.5 mg, 0.313 mmol) in DMF (0.9 mL) then added Hunig's base (0.137 mL, 0.784 mmol) and the reaction mixture was stirred at 20° C. for 1 h. Water (100 uL) was then added and the mixture was heated at 70° C. for 16 h, then diluted with 100 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (25 mg, 39.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.95 (m, 2H) 2.10-2.21 (m, 2H) 2.21-2.35 (m, 2H) 3.31 (s, 3H) 3.65 (s, 2H) 7.79 (d, J=8.6 Hz, 2H) 8.14 (d, J=6.1 Hz, 2H) 8.44 (d, J=6.6 Hz, 2H) 8.65 (s, 2H) 8.87-8.95 (m, 1H) 13.55 (br. s., 1H). MS m/z 404 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 61.4 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (298 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)pyrrolidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (332 mg, 61%) as a yellow solid: ESI MS m/z 540 [C26H30BrN5O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH:69]([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72]>O1CCCC1.O>[CH2:71]([O:70][CH:69]([O:73][CH2:74][CH3:75])[CH2:68][CH2:67][NH:66][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:18]=[CH:19][C:20]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=3[F:32])=[O:23])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:17])[CH3:72]
Reactant: CCOC(CCN)OCC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)OCC
Temperature: 60 °C

Procedure:
To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (1.0 g, 2.2 mmol) in 20 ml of anhydrous tetrahydrofuran were added HATU (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (620 mg, 4.8 mmol). The mixture was heated at 60° C. for 20 minutes, followed by addition of 1-amino-3,3-diethoxypropane (388 mg, 2.6 mmol). The mixture was heated at 60° C. for another 30 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as off-white solid. Yield: 1.23 g, 95%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Li]C.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH:26]([C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C=O)n1
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
To a solution of tert-butyl (6-bromopyridin-2-yl)carbamate (15.960 g, 58.43 mmol, 1 eq.) in 300 ml of THF cooled to −78° C. was added MeLi (1.6 M, 36.52 ml, 58.43 mmol, 1 eq.) dropwise and stirring allowed for 30 min. Then BuLi (1.6 M, 40.17 ml, 64.27 mmol, 1.1 eq.) was added dropwise and stirring allowed for 1 h. DMF (9.36 g, 128.55 mmol, 2.2 eq.) was added and the mixture was stirred 30 min at −78° C. and 1 h at r.t. The reaction was quenched with sat. aqueous NH4Cl, and DCM was added. The aqueous layer was extracted with DCM and then organics were combined, dried over MgSO4 and concentrated to give tert-butyl (6-formylpyridin-2-yl)carbamate (13.46 g) as a clear oil that was used directly in next step.
Reaction SMILES: BrC1C=C2C(=CC=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([O:24][CH3:25])[CH:18]=[CH:17]2>>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:5][CH2:6][C:7](=[O:12])[CH3:8])[CH:23]=[CH:22]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: Oc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(CCC(C)=O)ccc2c1

Procedure:
The process of claim 1 which also comprises methylating the 6-bromo-2-naphthol to 6-bromo-2-methoxynaphthalene and then converting the 6-bromo-2-methoxynaphthalene thus obtained to 4-(6-methoxy-2-naphthyl)-2-butanone.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]O)[CH2:4][CH2:3]1.[BrH:12]>S(=O)(=O)(O)O>[Br:12][CH2:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4]1
Reactant: Br
Reactant: CC1(C)CCC(CCO)CC1
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(CCBr)CC1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(4,4-dimethylcyclohexyl)ethanol (WO99/59971) (2 g, 12.8 mmol), concentrated sulphuric acid (750 μl) and 48% hydrobromic acid (3 ml) was stirred at 90° C. for 7 hours. The cooled mixture was then carefully quenched by the addition of water (25 ml), and the mixture was extracted with dichloromethane (3×30 ml). The combined organic extracts were washed with 2M sodium carbonate solution and brine (30 ml), then dried (MgSO4) and concentrated under reduced pressure. The residual black gum was purified by distillation to afford the title compound, 330 mg. 1H-NMR (CDCl3, 400 MHz) δ: 0.82 (2×s, 6H), 1.02-1.20 (m, 4H), 1.35 (m, 3H), 1.50 (m, 2H), 1.78 (m, 2H), 3.40 (t, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[CH:12]=[CH:11]2)[CH:7]=[C:6]([N:20]=[N+]=[N-])[N:5]=1)=[N+]=[N-].C.[H][H]>CCOC(C)=O>[CH3:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:10]([C:8]1[CH:9]=[C:4]([NH2:1])[N:5]=[C:6]([NH2:20])[CH:7]=1)[CH:11]=[CH:12]2
Reactant: Cc1cccc2ccn(-c3cc(N=[N+]=[N-])nc(N=[N+]=[N-])c3)c12
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Cc1cccc2ccn(-c3cc(N)nc(N)c3)c12
Reaction time: 24 h

Procedure:
A crude reaction mixture from the preparation of 1-(2,6-diazidopyridin-4-yl)-7-methyl-1H-indole G1 (approx. 340 mg, 1.2 mmol in 2 ml crude mixture) is diluted with EtOAc (10 ml). Under an atmosphere of nitrogen palladium on activated charcoal (10 mg, 10% Pd) is added. At RT the atmosphere is replaced by hydrogen (5 bar) and stirring is continued for 24 h. The mixture is filtered and extracted with an aqueous 0.5 mol/l sodium hydroxide solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 120 mg (43%). HPLC-MS: M+H=239; tR=0.81 min (Method—2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH:20]1([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.CO>[CH:20]1([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(CNCC2CCCCC2)cc1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CNCC2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-[(cyclohexylmethylamino)methyl]phenylamine hydrochloride. Yield: 60 mg (13% of theory); melting point: 205° C.-210° C.; C29H29ClN2O (M=457.01); calc.: molecular ion peak (M+H)+: 457/459 (Cl); found: molecular ion peak (M+H)+: 457/459 (Cl); Rf value: 0.60 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=O)[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>O1CCOCC1>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[S:22])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1c(=O)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: CCCCCn1c(=O)[nH]c(=S)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C
Yield: 17.5 %

Procedure:
A mixture of 3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione (0.81 g, 2.8 mmol) and phosphorus pentasulfide (1.2 g, 2.8 mmol) in 1,4-dioxane (20 mL) was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography twice (0-50% MeOH in CH2Cl2) to yield 0.15 g of pure product as a yellow solid (0.15 g, 18% yield). LCMS calculated for C11H14F3N4OS (M+H): 307.1; found: 307.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:27])[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1.COC[C@@H]1[C@@H](/C=C/C(/C)=C/C(OCC)=O)[C@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1>>[CH3:1][O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@:5]1([CH3:27])[C:15]1[CH:16]=[C:17]([CH:24]([CH3:25])[CH3:26])[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1
Reactant: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@@H](COC)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: COC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 70 %

Procedure:
Following a procedure similar to that for the preparation of Compound 28 but using Compound 27a as the starting material afforded the title compound (9 mg, 70% yield) as a white solid:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd]>[N:11]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cc(-n2ccnc2)ccc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.8 %

Procedure:
To 1-(3-methyl-4-nitro-phenyl)-1H-imidazole (200 mg, 0.98 mmol) and 10% Palladium on carbon (35 mg) was added degassed methanol (3 mL). The suspension was flushed and evacuated with hydrogen/vacuum line. The suspension was allowed to stir at room temperature for 14 h under hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was filtered through a pad of celite and rinsed with methanol. Concentration of the filtrate gave the title compound (166 mg, 98%) which was used for the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (1H, s), 7.48 (1H, s), 7.16 (1H, narrow d, J=2.5 Hz), 7.09 (1H, dd, J=2.5, 8.4 Hz), 7.01 (1H, s), 6.67 (1H, d, J=8.4 Hz), 5.03 (2H, broad s), 2.10 (3H, s).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[O:15]C.O>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(CC#N)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
BBr3 (17 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in dichloromethane (120 mL) at −78° C. under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (40 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 6.87 (dd, J=2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2OC(C)(C)C(C)(C)[O:20]2)=[C:15]([CH:28]=[O:29])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[BH4-].[Na+]>CO>[OH:20][B:19]1[C:16]2[CH:17]=[CH:18][C:13]([O:12][C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[F:1])=[CH:14][C:15]=2[CH2:28][O:29]1
Reactant: COC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc3c(c2)COB3O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of methyl 3-fluoro-4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate (5 g, 12.5 mmol) in MeOH (125 mL) was added NaBH4 (709 mg; 18.75 mmol) in portions under N2 at 0° C. in an ice-bath. The reaction was stirred at 0° C. to room temperature. The reaction was monitored with TLC and was completed overnight. The mixture was cooled to rt. Solvent was evaporated to half volume via Rota vapor. The mixture was then cooled to 0° C., and quenched by adding water (12 mL) following by adding 6 N HCl (12 mL). Stirred at rt for 30 min, white Solid precipitated out. Filtered. The solid was gummy. The solid was suspended in water, sonicated for 1 hr. Filtered, washed with more water. Filtered, dried to get white solid. D139 (2.1 g). Yield 55.7%. M.p. 149-152° C. MS (ESI): m/z=303 (M+1, positive) and 301 (M−1, negative). HPLC (220 nm): 97.27% purity. (254 nM): 97.29% purity 1H NMR (DMSO-d6, 300 MHz): δ=9.19 (s, 1H), 7.88 (dd, J=1.8, 11.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 4.93 (s, 2H), and 3.84 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]([C:16]2[C:17]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(O)C>C(OCC)(=O)C>[CH:1]1([NH:4][C:26]2[N:25]=[C:24]([CH2:23][S:22][C:17]3[C:16]([C:14]([NH:13][C:8]4[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH3:5])[CH:7]=4)=[O:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:29]=[CH:28][N:27]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(S(C)=O)n2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC3CC3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Cyclopropylamine (6.0 mL) was added to N-(3,5-dimethylphenyl)-2-(2-methylsulfinylpyrimidin-4-ylmethylthio)pyridine-3-carboxamide (990 mg, 2.4 mmol, Compound No. 1-27), and the mixture was stirred for 30 minutes at 80° C. The reaction mixture was diluted with ethyl acetate (80 mL), washed twice with water (50 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the residue was purified by silica gel column chromatography to give 650 mg (recrystallized from ethanol) of the target compound as a colorless solid (Yield: 67%).
Reaction SMILES: B(Br)(Br)Br.[C:5]1([C:11]2(C)[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([O:21]C)[CH:15]=[CH:16][CH:17]=3)[NH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:24](Cl)Cl>>[C:5]1([C:11]2[C:20]([CH3:24])=[CH:19][C:18]3[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: COc1cccc2c1NC(C)(c1ccccc1)C=C2
Agent: BrB(Br)Br
Product: Cc1cc2cccc(O)c2nc1-c1ccccc1
Reaction time: 3 h
Yield: 64 %

Procedure:
17.6 ml (180 mmol) of boron tribromide are added dropwise, at −30° C., to a solution of 21.2 g (85 mmol) of 2-phenyl-2-methyl-8-methoxyquinoline in 500 ml of methylene chloride. The cooling bath is then removed and the reaction medium is stirred for 3 hours until it has returned to ambient temperature. The reaction mixture is then poured onto ice and the medium is basified using sodium hydrogencarbonate. The medium is subsequently extracted with 3×200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane 3/7) to give 12.7 g of 2-phenyl-3-methyl-8-hydroxyquinoline in the form of a colorless oil. (Yield: 64%)