Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=O)[O:10]C2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:10])[CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 31.3 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (0.15 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil. Purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) followed by recrystallization from diethyl ether afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 32%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 89.21 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 7.52-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.30 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 511 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CN(C=O)C.C[O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].Cl>C1(C)C=CC=CC=1.O>[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(O)c(C(=O)O)cc1OC
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
In 20 g of toluene was suspended 6.28 g of AlCl3 in a stream of argon, to which 20 g of DMF was then added dropwise at 26° C. before adding 10.0 g of compound (1a), followed by heat stirring at 85° C. for 1.5 hours. The reaction mixture was cooled, to which 5.89 g of 35% hydrochloric acid was then added dropwise before adding 17.0 g of water, followed by heat stirring at 75° C. for one hour. The precipitated crystal was collected by filtration and washed with water. The resultant crystal was dried under reduced pressure at 60° C. to provide 9.0 g of compound (2a) at a yield of 96%.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:6][C:7]1[C:8]([CH2:16]Cl)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[NH:18][CH:5]1[C:4](=[O:3])[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:16][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)C(Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(NC1Cc2ccc3[nH]ncc3c2CN(Cc2ccncc2)C1=O)OCc1ccccc1

Procedure:
In a manner similar to [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamic acid benzyl ester, the title compound was prepared by treating 2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester, hydrochloride with 4-(aminomethyl)pyridine followed by treatment with acetic acid in refluxing toluene to give (8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester in 65% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([O:27]C)=[O:26])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=[O:26])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3cccs3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate (0.85 g, 1.8 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide solution (4 ml). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.79 g, 96.3%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:40][C:38]1[CH:39]=[C:34]([CH3:33])[N:35]=[C:36]([C:41]2([NH:44][C:26]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([CH3:32])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=3)=[O:27])[CH2:42][CH2:43]2)[N:37]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.17 g, 0.1 mmol, 3 eq) (60% purity), HOBT (0.046 g, 0.34 mmol, 1.0 eq), EDC.HCl (0.072 g, 0.37 mmol, 1.1 q) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylehtylamine (0.132 g, 1.0 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.44 (d, J=3.36 Hz, 2H), 1.51-1.54 (d, J=3.48 Hz, 2H), 2.32-2.34 (d, J=5.8 Hz, 9H), 2.81-2.82 (d, J=4.6 Hz, 3H), 4.0 (s, 3H) 7.0 (s, 1H), 7.15 (s, 1H), 7.34-7.42 (m, 3H), 7.52 (s, 1H), 7.72-7.74 (d, J=8.8 Hz, 2H), 7.97-8.02 (m, 2H), 8.46-8.48 (d, J=4.56 Hz, 1H), 8.91 (s, 1H). LCMS: (ES+) m/z=579.2 (M+H)+
Reaction SMILES: C([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15](OCC3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)CC.C([OH:29])C>[Pd]>[OH:11][C:10]1[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:29])[CH:13]=2)[CH2:7][C:6](=[O:26])[CH:5]=1
Reactant: CCO
Reactant: CCC(=O)C1=C(O)CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Agent: [Pd]
Product: O=C1C=C(O)CC(c2cccc(O)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (0.068 mol) of 2-propionyl-3-hydroxy-5-(4-benzyloxyphenyl)cyclohex-2-en-1-one in 250 mL of absolute ethanol was treated with 7.5 g of 5 percent palladium on carbon and shaken in a Parr® hydrogenator under 50 pounds of hydrogen pressure for 2 hours at room temperature. The reaction mixture was filtered through diatomaceous earth, diluted with 1 liter of water and extracted thrice with 100 mL portions of ethyl acetate. The combined extracts were washed with an aqueous saturated NaCl solution, dried over MgSO4, filtered, concentrated and cooled to precipitate the desired above named product as a greyish-white solid in a yield of 9.8 g (71 percent of theoretical). The product melted at 140°-150° C./ dec.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]([F:63])([F:62])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH2:42][CH2:43][NH:44][CH:45]3[CH2:54][CH2:53][CH2:52][C:51]4[N:50]=[C:49]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:48]=[CH:47][C:46]3=4)=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>C(#N)C>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]([CH2:3][CH2:2][N:44]([CH2:43][CH2:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:63])([F:20])[F:62])=[CH:23][CH:24]=3)=[CH:61][CH:60]=2)[CH:45]2[CH2:54][CH2:53][CH2:52][C:51]3[N:50]=[C:49]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:48]=[CH:47][C:46]2=3)=[CH:5][CH:6]=1)=[O:9]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
300 mg (1.04 mmol) of methyl 4-(2-iodoethyl)benzoate and 55 mg (0.52 mmol) of anhydrous sodium carbonate were added to a solution of 208 mg (0.35 mmol) of ethyl 5-[(2-{2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 155A) in 3 ml of dry acetonitrile, and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 140° C. for 4 h. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile/water 9:1). This gave 102 mg (0.13 mmol, 39% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[Si:10]([C:14]#[CH:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][Si:10]([C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(C=O)nc1
Temperature: 100 °C
Yield: 92.8 %

Procedure:
A solution of 5-bromopicolinaldehyde (1 g, 5.3 mmol), TMS-acetylene (1.04 g, 10.6 mmol) and triethylamine (4 mL) in THF (10 mL) was purged with argon for 10 min. Copper iodide (76 mg, 0.4 mmol), Pd(PPh3)2Cl2 (141 mg, 0.4 mmol) and triphenylphosphine (0.1 g, 0.4 mmol) was added and the mixture was heated to 100° C. under microwave irradiation for 10 min. Ethyl acetate (200 mL) was added at the solution was washed with water (2×25 mL), dried over MgSO4 and concentrated to dryness. The residue was filtered through silica gel with CH2Cl2 to give the title compound as a yellow oil (1 g, 95%). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.82 (s, 1H), 7.91 (s, 2H), 0.29 (s, 9H).
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]/1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[OH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH2:35])=[NH:34]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:35]=[C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][OH:23])[N:34]=[CH:4][C:5]=2[CH2:14]1
Reactant: CN(C)/C=C1\C[C@@H](c2ccccc2F)c2ccccc2C1=O
Reactant: N=C(N)Nc1ccccc1CCO
Product: OCCc1ccccc1Nc1ncc2c(n1)-c1ccccc1[C@H](c1ccccc1F)C2

Procedure:
This was synthesized by using general procedure 6 except that (R,E)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one reacted with 1-(2-(2-hydroxyethyl)phenyl)guanidine to give (R)-2-(2-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol. M.p.=162-163° C. 1H NMR 400 MHz (DMSO-d6) δ 9.05 (s, 1 H), 8.23-8.21 (m, 2 H), 7.81-7.79 (d, 1 H), 7.46-7.43 (m, 2 H), 7.30-7.22 (m, 4 H), 7.06-7.02 (m, 3 H), 6.82-6.77 (m, 1 H), 5.21 (t, J=4.4 Hz, 1 H), 4.65 (t, J=6.8 Hz, 1 H), 3.70-3.66 (m, 2 H), 3.19-3.04 (m, 2 H), 2.18 (t, J=6.0 Hz, 2 H). LCMS m/e 412 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12](N(CC)CC)[CH3:13].ICC.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:12][CH3:13])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN(CC)CC
Reactant: Sc1nc2cc(Cl)ccc2s1
Solvent: O
Solvent: CCI
Solvent: CCO
Product: CCSc1nc2cc(Cl)ccc2s1
Yield: 53.4 %

Procedure:
5-Chloro-2-mercaptobenzothiazole (20.17 g, 0.1 mol) in 55 ml 95% ethanol was treated with 10.1 g (0.1 mol) triethylamine to give a brown solution. Iodoethane (15.6 g, 0.1 mol) was added and the mixture refluxed 67 minutes. The mixture was cooled and poured into 300 ml water to precipitate a solid. The aqueous phase was extracted 3×50 ml methylene chloride. The organic extracts were combined with solid precipitate, washed with water, dried over Na2SO4, filtered, and rotary evaporated to give brown solid. Recrystallization from isopropanol yielded 12.26 g (53%) brown crystals, mp 49°-50° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
A solution of nickel (II) chloride hexahydrate (78 mg, 0.328 mmol) and (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (295 mg, 0.82 mmol) in methanol (8 mL) was cooled to 0° C. and then treated with sodium borohydride (186 mg, 4.92 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water (30 mL) and ethyl acetate (50 mL). The two layers were separated. The organic layer was washed successively with a 3N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid methyl ester (285 mg, 96%) as a viscous oil: EI-HRMS m/e calcd for C18H23ClN4O2 (M+) 362.1509, found 362.1516.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[CH2:5].C[N:14]=[C:15]=[O:16].[C:17]([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:10]([CH3:17])[C:15]([NH2:14])=[O:16])=[CH:11][CH:12]=1)=[CH2:5]
Reactant: CN=C=O
Reactant: CC(=O)[O-]
Reactant: C=C(COC)c1ccc(N)cc1
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: C=C(COC)c1ccc(N(C)C(N)=O)cc1
Reaction time: 20 h

Procedure:
To a solution of 8.2 g (0.05 Mol) 4-(1-methoxymethyl-ethenyl)aniline in 200 ml absolute diethylether are added, at ambient temperature, 4 ml (0.067 Mol) methylisocyanate. The resulting reaction solution is, after the addition of 0.3 g dibutyl tin diacetate, kept at room temperature for 20 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]=[C:22]([NH:25][C:26]3[N:31]=[CH:30][C:29]([S:32]CCC(OC)=O)=[CH:28][C:27]=3[O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[S:23][CH:24]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12].CC([O-])(C)C.[K+]>CS(C)=O>[O:39]([C:27]1[C:26]([NH:25][C:22]2[S:23][CH:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:11](=[O:13])[CH3:12])[CH2:19][CH2:18]3)[N:21]=2)=[N:31][CH:30]=[C:29]([S:32][C:2]2[C:3]3[CH:10]=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Clc1ncnc2sccc12
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ncnc5sccc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-chlorothieno[2,3-d]pyrimidine (0.050 g, 0.29 mmol) and methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (0.15 g, 0.29 mmol) were dissolved in DMSO (3 mL). The solution was degassed for 15 minutes. KOtBu (0.098 g, 0.88 mmol) was added and the reaction stirred at room temperature for two hours. The solution was quenched with water, extracted with dichloromethane, dried, and concentrated. Flash chromatography gave the title compound (0.075, 46%). 1H NMR (400 MHz, CDCl3) δ 1.60-1.72 (m, 2H), 2.08-2.15 (m, 2H), 2.11 (m, 3H), 2.65-2.75 (m, 1H), 2.82-2.93 (m, 1H), 3.15-3.24 (m, 1H), 3.91 (d, 1H), 4.72 (d, 1H), 6.49 (s, 1H), 7.15 (d, 2H), 7.19 (t, 1H), 7.27-7.29 (m, 1H), 7.36-7.42 (m, 3H), 7.53 (d, 1H), 8.27 (d, 1H), 8.68 (s, 1H), 8.81 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:30]1([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2c(c1O)c(-c1ccccc1)c(-c1ccc(F)cc1)n2-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 3-bromo-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (180 mg, 0.395 mmol), phenyltributlytin (149 μL, 0.454 mmol), and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in DMF (2 mL) was stirred at 130° C. overnight. Then the mixture was diluted with EtOAc, washed with water and saturated NaCl aqueous solution respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, the residue was purified by column and prep TLC to give a white solid, the desired title compound (59 mg). The title compound, ESI MS (m/z): 453 (M+H+).
Reaction SMILES: N[C:2]1[O:3][C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1C=O.[C:15]([C:17]#[CH:18])#[N:16].[CH3:19][N:20](C)C=O>>[C:15]([C:17]1[CH:19]=[N:20][C:7]2[C:6](=[O:10])[C:5]3[C:4]([O:3][C:2]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)#[N:16]
Reactant: C#CC#N
Reactant: Nc1oc2ccccc2c(=O)c1C=O
Reactant: CN(C)C=O
Product: N#Cc1cnc2c(=O)c3ccccc3oc2c1
Temperature: 140 °C
Reaction time: 15 h

Procedure:
To 70 ml of dimethylformamide was added 2.2 g of 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehyde, followed by the addition of 2.5 g of cyanoacetylene. The mixture was heated under stirring at 140° C. for 15 hours and the solvent was then distilled off under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform and recrystallized from acetonitrile to give 0.83 g of 3-cyano-1-azaxanthone as crystals, m.p. 220°-226° C.
Reaction SMILES: C(SCC1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](C3C=CC=CC=3)[CH:14]=2)[NH:9]C(C)(C)C=1)C=C.Br[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[CH:34]=2)[NH:29][C:28]([CH3:45])([CH3:44])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(S)C=C>>[CH3:43][O:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:45])([CH3:44])[CH:27]=[C:26]2[CH2:25][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: C=CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Allylsulfanylmethyl-2,2-dimethyl-6-phenyl-1,2-dihydroquinoline 40 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 44 μL of allyl mercaptan reacted to give 5 mg of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25])#[N:15].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:8][C:6]1[N:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[C:17]([F:25])[CH:18]=2)[CH:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=1
Reactant: CC(C)(C)Nc1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Into a 25 mL sealable tube under nitrogen were combined 6-chloro-N4-(1,1-dimethylethyl)-2,4-pyrimidinediamine (440 mg, 2.19 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.416 g, 2.52 mmol) in 1,4-dioxane (8 mL). Saturated aqueous NaHCO3 (4 mL) was added, and the resulting mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (0.127 g, 0.11 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 95° C. overnight. The reaction was cooled to room temperature, solids and other insoluble impurities formed during the reaction were filtered, and the orange filtrate was concentrated. The resulting solid was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in DMSO and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA). Fractions were evaporated and solids were triturated in Et2O and filtered to afford the title compound (553 mg). LC-MS (ES) m/z=286 [M+H]+.