Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][C:16]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: C1CCNC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1CCCC1
Reaction time: 0.25 h

Procedure:
A solution of pyrrolidine (35 grams; 0.5 mol) and triethylamine (50 grams; 0.5 mol) in benzene (500 ml) is placed in a glass reaction flask equipped with a mechanical stirrer and reflux condenser. β-Chloropropionyl chloride (64 grams; 0.5 mol) is then slowly added with stirring over a period of about 15 minutes. Stirring is continued for a period of about 30 minutes. After this time the reaction mixture is first filtered to remove triethylamine hydrochloride nd is the stripped of benzene to yield 1-(β-chloropropionyl) pyrrolidine.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([F:38])[C:31]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:43]3[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:31]4[C:32]([F:38])=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=4[F:29])[N:44]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxy carbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (13.6 mg, 0.035 mmol), 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.032 mmol), HATU (30.2 mg, 0.080 mmol) in DMF (0.07 mL) and DIPEA (0.017 mL, 0.095 mmol) was stirred at room temperature for 16 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (5.0 mg, 24%). LCMS calc. for C33H37F3N5O6 (M+H)+: m/z=656.3. Found: 656.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH2:9]1)=[O:7].I[Si](C)(C)C.[NH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Ba+2]>C(Cl)(Cl)Cl>[N:29]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9][CH2:10]2)[C:38]2[CH:33]([CH2:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1OC
Reactant: c1ccc2c(c1)CCCN2
Agent: C[Si](C)(C)I
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CCC(N3CCCC4CC=CC=C43)c3ccccc32)cc1OC
Reaction time: 2 h
Yield: 36.7 %

Procedure:
1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.28 mmol) prepared in Reference Example 2 was dissolved in chloroform (10 ml), to which iodotrimethylsilane (638 mg, 3.19 mmol) was then added on ice and stirred for 2 hours. After the reaction mixture was concentrated, the residue was dissolved in THF (10 ml) and mixed with 1,2,3,4-tetrahydroquinoline (511 mg, 3.84 mmol) and barium carbonate (505 mg, 2.56 mmol), followed by stirring at room temperature for 48 hours. After the reaction mixture was filtered to remove insoluble products and concentrated, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/3) and the resulting eluate was recrystallized from diethyl ether-hexane to give the product of interest, i.e., 4-(tetrahydroquinolin-1-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-quinoline (202 mg, yield: 37%) as a white crystal.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=2[Cl:14])=[N:5][N:6]=1.[CH3:15][N:16]1[CH2:23][C@@H:22]2[C@@H:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:14][C:8]1[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([N:20]2[CH2:21][C@@H:22]3[C@@H:18]([CH2:17][N:16]([CH3:15])[CH2:23]3)[CH2:19]2)=[N:6][N:5]=1
Reactant: Clc1cc(I)ccc1-c1nnc(Br)s1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN1C[C@@H]2CN(c3nnc(-c4ccc(I)cc4Cl)s3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2-bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole (600 mg, 1.49 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (377 mg, 2.99 mmol) in NMP (4 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was cooled to room temperature then saturated NaHCO3(aq) (30 mL) was added. The resulting suspension was left to slurry for 1 hour before filtering under vacuum to afford the title compound as a pale brown solid which was used in the next step without further purification. LC-MS: Rt 1.06 min; MS m/z 446.8 [M]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.77-7.86 (m, 2H), 3.71 (t, J=8.84 Hz, 2H), 3.36 (br. s., 2H), 2.97 (br. s., 2H), 2.40-2.54 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]2=[O:24])[N:8]=1.[Cu][C:26]#[N:27].CN(C=O)C>Cl.[Fe](Cl)(Cl)Cl>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:26]#[N:27])[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2Br)n1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2C#N)n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A round-bottomed flask equipped with a nitrogen inlet and a reflux condenser was charged with 1-(2-(4-(3-bromothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazol-idine-2,4-dione (50 mg, 0.12 mmol), copper (I) cyanide (33 mg, 0.36 mmol), and dry DMF (2 mL). The reaction mixture was heated to reflux (bath temperature 160° C.). After 4 h, the reaction vessel was removed from the oil bath and allowed to cool to approximately 70° C. and poured into a stirring suspension of iron (III) chloride (0.28 g, 1.70 mmol) in 1.7 N aqueous HCl (5.0 mL). The combined mixture was maintained at 60-70° C. for 30 min at which time the mixture was allowed to cool to ambient temperature and extracted with three 15 mL portions of dichloromethane. The combined extracts were washed with two 40 mL portions of 6 N aqueous HCl, saturated aqueous NaHCO3, and H2O, then dried over Na2SO4 and concentrated. Chromatographic purification by preparative TLC, eluting with 8% MeOH/dichloromethane, and subsequent crystallization from EtOAc afforded the product as a white solid. MS (M+H)+ 357.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.ClCCl>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH3:14]
Reactant: CCN(CC)CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-nitrobenzoic acid (2.00 g, 11.9 mmol), N,N-diethylethylene diamine (1.53 g, 13.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.74 g, 14.35 mmol), and 1-hydroxybenzotriazole hydrate (2.19 g, 14.35 mmol) in 15 mL DMF was stirred at room temperature for 4 hours. The mixture was diluted with dichloromethane (100 mL) and washed with aqueous saturated sodium bicarbonate solution (50 mL). The aqueous layer was re-extracted with dichloromethane (2×50 mL) and the combined organic solutions were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude mixture was purified on silica gel column to provide N-(2-(diethylamino)-ethyl)-4-nitrobenzamide as an amber colored oil (2.2 g 69%).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C=O)C.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[O:4][C:5]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nc2ccc(CO)cc2o1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc2ccc(CCl)cc2o1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
To a stirred solution of (2-(methylthio)benzo[d]oxazol-6-yl)methanol (2 g, 10.26 mmol) from Step 2 of this Example in a mixture of anhydrous DMF (0.5 mL) and anhydrous DCM (100 mL) at 0° C. was added dropwise thionyl chloride (4 mL, 55 mmol). The mixture was allowed to warm to rt and stirred for a further 40 min. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated aq NaHCO3 and a 10:1 mixture of DCM:MeOH. The organic layer was separated and dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (2 g, 92%) as a light pink solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.75 (d, J=1.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.43 (dd, J=1.3, 8.1 Hz, 1H), 4.89 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 214 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[S:42][C:16]2[N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:18](=[O:26])[N:19]([CH:22]([CH3:25])[CH2:23][OH:24])[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[S:42][C:16]2[N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:18](=[O:26])[N:19]([CH:22]([CH3:25])[CH:23]=[O:24])[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12]
Reactant: CCc1cc2c(=O)n(C(C)CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(C(C)C=O)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a mixture of oxalylchloride (0.43 mL) and methylene chloride (10 mL) were added a solution (10 mL) of dimethyl sulfoxide (0.35 mL) in methylene chloride and a solution (10 mL) of 4′-{[6-ethyl-3-(2-hydroxy-1-methylethyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (2 g) in methylene chloride at −78° C., and the mixture was stirred at the same temperature for 15 min. Triethylamine (3.14 mL) was added, and the mixture was allowed to warm to room temperature. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.7 g, 85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:34])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][C:27]([F:31])=[CH:28]2)[C:24]([CH3:33])([CH3:32])[CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[CH3:32][C:24]1([CH3:33])[C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:34])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22][CH2:23]1)[CH:28]=[C:27]([F:31])[CH:26]=2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c3cc(F)cc1c32

Procedure:
Beginning with (indol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CCO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: C1CNCCNC1
Solvent: CC(=O)Cl
Solvent: CCO
Product: Clc1ccc(CN2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Acetyl chloride (11.7 mL, 0.165 mol) was added to anhydrous EtOH (500 mL) and the mixture was stirred for 30 min at 25° C. Homopiperazine (15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4 h. 4-Chlorobenzyl chloride (13.96 g, 0.087 mol) was added and the reaction mixture was heated to reflux for 16 h before concentrating. The residue was dissolved in EtOAc (500 mL) and washed with 1N aqueous KOH (50 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (double separation. SiO2, 20×7 cm, 1PrOH—H2O—NH4OH, 80:12:6 to 70:20:10 gradient elution) afforded the desired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36 g, 16.5%). GC/MS m/e 224 (M+, C12H17N2Cl).10% CH3OH—CH2Cl2); RPLC tR=5.96 min (>85%), 220 nm (Mm (Method B): ESI/MS m/e 498.3 (MH++H, C31H35N3O3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[O:31]CC1C=CC=CC=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[OH:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cccc(OC)c1OCc1ccccc1
Solvent: CCOCC
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cccc(OC)c1O

Procedure:
Following a similar procedure to that described in Preparation 124, but using N-(2-t-butyl-5-carbamoylphenyl)-3-(2-benzyloxy-3-methoxyphenyl)-octanamide (prepared as described in Example 119), the title compound was obtained as crystals, melting at 118°-121° C. (from diethyl ether).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:20][CH:19]2[CH2:21][CH:11]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:22][CH3:23])[CH:16]=[CH:17][C:18]=32)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[CH2:22]([C:15]1[CH:16]=[CH:17][C:18]2[CH:19]3[CH2:21][CH:11]([CH2:12][C:13]=2[CH:14]=1)[CH2:10][NH:9][CH2:20]3)[CH3:23]
Reactant: CCc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: CCc1ccc2c(c1)CC1CNCC2C1
Yield: 63.8 %

Procedure:
11-Benzyl-5-Ethyl-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene hydrochloride (160 mg, mmol), ammonium formate (220 mg, 3.49 mmol) and 10% Pd(OH)2/C (100 mg) were combined in methanol (MeOH) (5 mL) and warmed to reflux for 15 min. The mixture was cooled, filtered, concentrated, diluted with sat. aq. Na2CO2 soln. and extracted with EtOAc (3×20 mL). The extracts were dried (MgSO4), filtered and concentrated to an oil (94 mg, 83%). (TLC 50% EtOAc/hexanes (NH3) Rf 0.20). 1H NMR (CDCl3) δ 6.90 (d, J=9.0 Hz, 1H). 6.66 (2H), 3.97 (m, 2H), 3.08 (dd, J=18.0, 6.0 Hz, 1H), 2.94 (m, 3H), 2.76-2.65 (3H), 1.96 (m, 2H), 1.88 (d, J=11.0 Hz, 1H), 1.38 (t, J=7.0 Hz, 3H). This material was dissolved in excess 1N HCl MeOH and concentrated. Recrystallization from CH2Cl2/Et2O provided a solid (74 mg, 68%). mp 243-245° C.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([NH2:28])=[CH:21]2>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([N:28]=[C:1]=[S:2])=[CH:21]2
Reactant: Nc1cc2cc(Br)ccc2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc2cc(Br)ccc2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.251 g, 1.080 mmol) in dichloromethane at room temperature was added 6-bromoisoquinolin-3-amine (0.241 g, 1.080 mmol). The solution was stirred at room temperature for 3 hours. LC/MS indicated formation of the desired product. The deep orange solution was purified by silica gel chromatography (0-10% ethyl acetate-hexanes) to afford: 6-bromo-3-isothiocyanatoisoquinoline (0.1 g, 0.377 mmol, 35% yield) as a yellow oil. R.T.=2.54; [M+H]+=267.04.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
2-(3-Cyano-4fluorophenyl)acetic acid (4.0 g, 22.3 mmol) was diluted with THF (10 mL) and methanol (2 mL), placed under nitrogen and cooled to 0° C. TMSCHN2 (16.7 mL, 33.5 mmol) was added dropwise and the reaction was stirred for 30 minutes. The reaction was quenched with water and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using a Biotage 40M cartridge eluting with hexanes ethyl acetate (9.1) to yield methyl 2(3-cyano-4-fluorophenyl)acetate (1.76 g, 9.11 mmol, 41%) as clear oil that solidified to a white solid. 1H NMR (400 MHz, CDCl3) δ 7.48-7.59 (m, 2H), 7.19 (t, J=8.2 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH3:17])[CH:15]=O>C(Cl)(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:12]=[CH:13][N:14]([CH3:17])[CH3:15])#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Temperature: 170 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
—Fifteen grams of 5-nitroanthranilonitrile (compound 1, 92 mmol) was added to 25 ml of N,N-dimethylformamide in 200 ml of chloroform and the reaction mixture was heated under reflux for 5 hrs at 170° C. After cooling the reaction mixture at room temperature for 30 min and at 4° C. for 1 hr, the solid residue was washed with diethyl ether to give 19.23 g of compound 2 (yield, 96%). 1H-NMR (300 MHz, d6-DMSO): δ 8.48 (s, 1H), 8.27 (s, 1H), 7.38 (s, 1H), 3.06 (s, 3H), 3.17 (s, 3H).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Reactant: COc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3ccc(OC)cc3)cn2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
10 mg cupper (I) iodide, 20 mg trans-N,N′-dimethyl-1,2-cyclohexyldiamine was added to 1.1 g 4-(4-methoxy-phenyl)-1H-imidazole, 1.5 g 1-iodo-4-methoxy-benzene and 1.95 g cesium carbonate in 5 mL DMF under argon. The reaction was stirred 48 h at 120° C. in a closed microwave bottle under argon. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography on Alox (50 kg, Merck (Darmstadt), Bestell-Nr. 1.01097.9050 activity: II-III) (gradient: dichlormethane/EtOAC 9:1-8:2) to yield 1 g of the desired compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:18][CH2:19][CH2:20][O:21][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)=[CH:7][C:8]=1[C:14]([F:16])([F:17])[F:15])#[N:11]
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 432 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([Cl:15])[C:3]=1[C:4]#[N:5].C(OC([NH:23][C@@H:24]([CH3:27])[CH2:25]O)=O)(C)(C)C>>[NH2:23][C@@H:24]([CH3:27])[CH2:25][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([Cl:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1c(Cl)cc(-c2ccn[nH]2)cc1Cl
Product: C[C@H](N)Cn1ccc(-c2cc(Cl)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared from 2,6-dichloro-4-(1H-pyrazol-5-yl)benzonitrile (0.75 g, 3.15 mmol) and (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (0.552 g, 3.15 mmol) using the method of Example 34(c). Yield 0.121 g. 1H NMR (400 MHz; CDCl3): δ 1.15 (d, 3H), 1.54 (bs, 2H), 3.49 (m, 1H), 3.93 (dd, 1H), 4.14 (dd, 1H), 6.60 (d, 1H), 7.50 (d, 1H), 7.84 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45](OS(C(F)(F)F)(=O)=O)=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([CH:10]=[CH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: PCCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
Triethylamine (33 mg, 0.33 mmol) and tert-butyl acrylate (77 mg, 0.6 mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) were added to a solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the addition was complete the reaction flask was purged with argon. The mixture was stirred at 80–85° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH6 with 2M hydrochloric acid. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/ether (95/5). After removal of the solvent under vacuum, the solid was triturated with pentane/ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (63 mg, 49%).