Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:32][O:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=[C:36]([N:49]([CH3:51])[CH3:50])[N:35]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:39]4[C:34]([O:33][CH3:32])=[N:35][C:36]([N:49]([CH3:50])[CH3:51])=[N:37][CH:38]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)[CH:19]=1
Reactant: COc1nc(N(C)C)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N(C)C)ncc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 4-[2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-2-fluoro-benzonitrile (Intermediate BC) and 4-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate W) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 0.93 min (HPLC 3); ESI-MS: tR=1.03 min, [M+H]+576/578 (LC-MS 1); TLC: Rf=0.07 (EtOAc).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC>C(Cl)Cl>[CH:4]1[C:3]2[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][O:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1COc1ccccc1
Agent: FB(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2ccccc2COc2ccccc21
Temperature: 40 °C
Yield: 97.8 %

Procedure:
The 2-(phenoxymethyl)benzoic acid (22.18 g, 97 mmol) was dissolved in DCM (200 mL) and trifluoroacetic anhydride (20.59 mL, 146 mmol) was added, followed by a catalytic amount of borontrifluoride etherate (2.22 mL, 17.5 mmol). The reaction mixture was heated at 40° C. for 2 hours. The solution was then washed with water, sodium bicarbonate (saturated solution) and water. The organic phases was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on silica gel (10-20% ethyl acetate in hexanes) to afford title compound 482 (19.937 g, 98%) as a light pink solid. MS (m/z): 211.1 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].[SH:14][CH2:15][CH2:16]O.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[O:4]1[C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][S:14][CH2:15][CH2:16]1
Reactant: OCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29 %

Procedure:
A solution of ethyl 2-chloroacetyl-2-methoxyiminoacetate (65 g.) in dry chloroform (130 ml.) was added to a stirred mixture of 2-mercaptoethanol (25 g.), triethylamino (35 g.) and dry chloroform (70 ml.) at 20° C. over 30 minutes, and stirred at the same temperature for 2.5 hours. After the solution was adjusted to pH 1.0 with 10% hydrochloric acid under ice cooling, the chloroform layer was separated, washed with water twice and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C. to give yellow oil. The oil was dissolved in toluene (600 ml.), and then p-toluenesulfonic acid (5.5 g.) was added to the toluene solution. The solution was heated under reflux for 2 hours while removing the produced water. The resultant solution was allowed to cool at room temperature and filtered. The filtrate was washed with water (100 ml.) three times, a saturated aqueous solution of sodium bicarbonate (100 ml.) twice and water (100 ml.) twice in turn, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel "Kieselgel 60" [Trademark: manufactured by E. Merck] (1 kg.) and eluted with benzene. After the eluate was concentrated under reduced pressure, the residue was washed with diisopropyl ether and dried to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 21 g.), pale yellow crystals, mp. 64° to 66° C.
Reaction SMILES: [I-].[CH:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N+:14]([CH3:17])([CH3:16])C)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:18]1C=CN=[CH:19]1.[ClH:23]>C(O)C.CCOCC>[ClH:23].[CH:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:14]2[CH:16]=[CH:19][N:18]=[CH:17]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: c1c[nH]cn1
Reactant: C[N+](C)(C)Cc1cccn1C1CCCCC1
Agent: Cl
Agent: [I-]
Solvent: CCOCC
Solvent: CCO
Product: c1cc(Cn2ccnc2)n(C2CCCCC2)c1

Procedure:
A solution of (1-cyclohexyl-pyrrol-2-yl)methyl trimethylammonium iodide (3.48 g) and imidazole (0.68 g) in ethanol (70 ml) was heated under reflux for 3 hours. The solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave an oil which was dissolved in ether. An excess of ethereal hydrogen chloride was added and the resulting solid was filtered off and crystallised from methanol/ethyl acetate to give 1-cyclohexyl-2-(imidazol-1-ylmethyl) pyrrole hydrochloride as a hygroscopic solid (0.80 g), m.p. 147°-149°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].Br[CH2:7][C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[CH:9]=1.O>C1C=CC=CC=1.CO>[CH:22]1[C:10]2[CH:9]=[C:8]([CH2:7][N:2]([CH3:1])[CH2:3][C:4]#[CH:5])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=[CH:20][CH:21]=1
Reactant: C#CCNC
Reactant: BrCC1=Cc2ccccc2Oc2ccccc21
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: C#CCN(C)CC1=Cc2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Methylpropargylamine (4.5 g, 65 mmol) is dissolved in benzene (75 ml) and methanol (25 ml). At 40° C. a solution of 10-bromomethyldibenz[b,f]oxepine (7.0 g, 25 mmol) in benzene (25 ml) is added dropwise in the course of half an hour. When the addition is complete, the mixture is stirred for a further half hour at 40°-50° C., poured into water, washed three times with water and then extracted with 5% methanesulfonic acid. The acidic aqueous phase is rendered basic with concentrated ammonia and extracted with diethyl ether. The ethereal phase is dried over sodium sulfate and concentrated by evaporation. Crystallisation of the residue from petroleum ether yields N-(dibenz[b,f]oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine alias 10-(N-propargyl-N-methyl-amino)methyldibenz[b,f]oxepine (5.3 g, 77%). Melting point: 66°-67° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[F:38][C:39]([F:54])([C:50]([F:53])([F:52])[F:51])[C:40]([F:49])([F:48])[C:41]([F:47])([F:46])[S:42](F)(=[O:44])=[O:43]>O.[Cl-].[Na+].O>[F:47][C:41]([F:46])([S:42]([O:26][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:23])[CH3:24])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:44])=[O:43])[C:40]([F:48])([F:49])[C:39]([F:54])([F:38])[C:50]([F:53])([F:52])[F:51]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Reaction time: 0.17 h

Procedure:
A 25-mL flask was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (437.24 mg, 1.244 mmol), cesium carbonate (446 mg, 1.369 mmol), and DMF (6222 μL). The resulting mixture was stirred for 10 min, then the vial was submerged in an ice-bath for 10 min. nonafluorobutanesulfonyl fluoride (241 μL, 1.369 mmol) was added dropwise over 1 min. The mixture was stirred for 3 hours before being diluted with water (20 mL) and a small amount of brine. This mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on an 80-g Redi-Sep column, eluting with 0-60% of a 90:10 mixture of DCM/MeOH in DCM to give (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]
Reactant: NCCCCCN1CCCCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 5-(piperidin-1-yl)-pentylamine (reference example 93c) and and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 536 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:4]=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[CH:4]([C:3]1[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5]
Reactant: CCOC(=O)CCCCBr
Reactant: O=Cc1c(O)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1cccc(OCc2ccccc2)c1C=O
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-hydroxy-6-benzyloxybenzaldehyde (3.0 g, 0.013 M), ethyl 5-bromopentanoate (2.75 g, 0.013 M), anhydrous potassium carbonate (2.16 g, 0.0156 M), sodium iodide (0.195 g) and dry dimethylformamide (15 ml) were stirred at 60°-80° C. for 3 hours and then left to stir at room temperature overnight. The mixture was then poured into water (50 ml) and the product extracted with ether (2×80 ml) and the combined extracts washed with 10% aqueous sodium hydroxide (2×20 ml) and then with water to neutrality, dried, and evaporated to give ethyl 5-(2-formyl-3-benzyloxyphenoxy)pentanoate, (4.0 g, 86%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[CH:2].[CH3:11][NH:12][CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCCl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]([CH3:13])[CH3:11])=[CH:5][CH:4]=1)#[CH:2]
Reactant: CNC
Reactant: C#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
Glacial acetic acid (3 drops) was added to a mixture of 4-ethynylbenzaldehyde (250.7 mg, 1.93 mmol), dimethylamine (2M in THF, 1.5 mL, 3.0 mmol) and NaBH(OAc)3 (617 mg, 2.91 mmol) in DCE (6.5 mL). The resulting mixture was stirred for 2.5 h at rt. The reaction was quenched with saturated aqueous NaHCO3 (˜40 mL). The product was extracted into CH2Cl2 (100 mL, then 2×50 mL), and the combined organic layer was washed with brine (25 mL), dried (Na2SO4) and evaporated in vacuo. Purification on Biotage Isolera (silica, 0-3% 2M NH3-methanol/CH2Cl2) gave 1-(4-ethynylphenyl)-N,N-dimethylmethanamine (280.1 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 3.42 (s, 2H), 3.07 (s, 1H), 2.24 (s, 6H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:2][CH3:1]
Reactant: CN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
5.1 g of methylamine is condensed in a solution of 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 35 ml of anhydrous tetrahydrofiran at -78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at -20° C., it was allowed to reach room temperature to be able to evaporate excess methylamine. Then, the reaction solution is added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.7 g of 11β-fluoro-3-hydroxy-7α-[5-(methylamino)-pentyl]-estra-1,3,5(10)-trien-17-one is obtained as crude product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[Br-:29].[Li+]>CC(C)=O.CCOCC>[Br:29][CH2:12][CH2:13][CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propyl 4-methylbenzenesulfonate, prepared in the previous step, in acetone (100 mL) was added lithium bromide (17.83 g, 205 mmol). The reaction mixture was stirred at room temperature for 17 h, and concentrated. The crude reaction mixture was diluted with Et2O, washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0% to 20% EtOAc in hexanes) gave 3-bromo-1,1-bis(4-fluorophenyl)propane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:16])[N:5]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][O:2][C:3]1[C:4](=[O:16])[N:5]([CH:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1cccn(C2CCC(=O)CC2)c1=O
Product: COc1cccn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-methoxy-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH2:1]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][C:25]([O:27]CC2C=CC=CC=2)=[O:26])[CH:14]=1)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>CO.O1CCOCC1.[C].[Pd]>[CH2:1]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:14]=1)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOC(=O)c1cn(CCCC(=O)OCc2ccccc2)c2ccccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCOC(=O)c1cn(CCCC(=O)O)c2ccccc12
Yield: 82978.3 %

Procedure:
A mixture of benzyl 4-(3-nonyloxycarbonyl-1-indolyl)butyrate (368 mg) obtained in Ex. 62 and 10% palladium carbon (0.10 g) in methanol and 1,4-dioxane was stirred at room temperature for 2 hours under a hydrogen atmosphere at 3 atm. Removal of the catalyst and evaporation of the solvent afforded 4-(3-nonyloxycarbonyl-1-indolyl)butyric acid (246 g) as a solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 18 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 52 (18% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.63 and 2.91 (2t, 2H), 3.51 and 4.04 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.40 and 4.93 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.74-8.01 (m, 4H), 8.10-8.16 (m, 1H), 8.20-8.26 (m, 1H), 8.67 and 8.72 (2s, 1H), 8.73-8.85 (m, 2H); MS (ESI) m/z 480 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][NH:5][C:6](=[O:11])OC(C)=C.[NH2:14][C:15]1[C:16]([F:34])=[CH:17][C:18]([F:33])=[C:19]([C:21]2[CH:32]=[N:31][C:24]3[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)[CH:20]=1.CN1CCCC1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[F:34][C:16]1[CH:17]=[C:18]([F:33])[C:19]([C:21]2[CH:32]=[N:31][C:24]3[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)=[CH:20][C:15]=1[NH:14][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:12])[CH3:13])=[O:11]
Reactant: CNc1ncc2cc(-c3cc(N)c(F)cc3F)cnc2n1
Reactant: C=C(C)OC(=O)NCCC(C)(C)C
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)cnc2n1
Temperature: 65 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
Treat a solution of prop-1-en-2-yl (3,3-dimethylbutyl)carbamate (0.039 g, 0.209 mmol) and 6-(5-amino-2,4-difluorophenyl)-N-methylpyrido[2,3-d]pyrimidin-2-amine (0.060 g, 0.209 mmol) in dioxane (5 mL) with catalytic 1-methylpyrrolidine (1.8 mg, 0.021 mmol) and heat at 65° C. overnight. Add 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.1 mL) and additional prop-1-en-2-yl (3,3-dimethylbutyl) (25 mg, 0.135 mmol) and heat the mixture at 85° C. overnight. Add additional 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.1 mL) and prop-1-en-2-yl (3,3-dimethylbutyl) (25 mg, 0.135 mmol) and heat the mixture at 85° C. for another 24 h. Cool the mixture to RT, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hexane). Treat the resulting material with DCM, allow to stand at RT overnight, and collect the solid via filtration to afford 1-(2,4-difluoro-5-(2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (30 mg, 35% yield). MS (m/z): 415.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]N(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CO>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and 4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, 1N phosphoric acid, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>CN1CCCC1=O>[N:10]1([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]#[N:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccnc(N2CCOCC2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 71.1 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and morpholine (0.7 ml, 8.0 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 2.5 hrs and combined with water to give precipitates, which were collected by filtration and dried to give the titled compound (0.39 g, 70%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]=[C:16]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([CH2:26][Cl:27])=[CH:22][CH:21]=3)[S:17][C:13]=2[C:12]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.O.CO>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([NH:18][C:16]2[S:17][C:13]3[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:11][CH:10]=[C:9]([OH:8])[C:14]=3[N:15]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Nc1nc2c(OCc3ccccc3)ccc(N3CCOCC3)c2s1)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nc2c(O)ccc(N3CCOCC3)c2s1)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
N-(4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamide (1.0 g, 2.0 mmol) were dissolved in CH2Cl2 (10 ml) and treated at −78° C. with tetrabutyl ammonium iodide (0.95 g, 2.6 mmol) and a solution of boron trichloride in CH2Cl2 (1M, 7.4 ml). After subsequent warming to 0° and stirring for additional 2 h, ice (2 g) and then water (10 ml) and methanol (2 ml) were added and the phases separated. The aqueous phases were extracted twice with CH2Cl2/MeOH, the combined organic layers were dried with Na2SO4 and evaporated to dryness. Recrystallization from CH2Cl2/MeOH afforded the title compound as an off-white solid (18%). MS: m/e=403 ([M−H+]−).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14]1[NH:19][C:18](=[O:20])[C:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](C)[CH:23]=2)=[CH:16][N:15]=1.[CH3:29]C1C=C(C=CC=1)CC1C(=O)NC(=S)NC=1>>[ClH:1].[ClH:1].[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14]1[NH:19][C:18](=[O:20])[C:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:29])=[CH:26][CH:27]=2)=[CH:16][N:15]=1
Reactant: Cc1cccc(Cc2c[nH]c(=S)[nH]c2=O)c1
Reactant: Cc1cccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Agent: Cl
Product: Cc1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cc1

Procedure:
In a similar manner 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methylbenzyl)-4-pyrimidone dihydrochloride m.p. 203.5°-205° (ex ethanol) may be prepared from 5-(3-methylbenzyl)-2-thiouracil.