Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
2.86 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 10 g of piperazine in 30 cm3 of dimethylsulphoxide were stirred and heated to 110° C. After two hours, the reaction was complete. After evaporation of the solvent under a good vacuum, the residue was taken up in 20 cm3 of water. The solid which precipitated was filtered off and recrystallised from 50 cm3 of a mixture of ethanol (1 volume) and methyl cellosolve (1 volume), which enabled an insoluble impurity, which was separated off by filtration of the hot solution to be removed. The crystals, which precipitated on cooling, were filtered off and recrystallised from the same solvent mixture. 1.2 g of 6-chloro-1-ethyl-4-oxo-7-piperazinyl-1,4-dihydro-quinoline-3-carboxylic acid were obtained; m.p. 228°-232° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3ccncc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M61) (0.27 g, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (133 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A mixture of 4-fluoroaniline (1.0 g, 8.99 mmol), 2-bromoethanol (2.25 g, 17.99 mmol), potassium carbonate (2.49 g, 17.99 mmol), and anhydrous N,N-dimethylformamide (4 mL) was added to a 50 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at 80° C. for 18 hours. Progress of the reaction was monitored by TLC using ethyl acetate:hexanes (1:1) (Rf product=0.4). The reaction was partitioned using ethyl acetate (80 mL) and water (30 mL). The organic layer was washed with saturated aqueous NaCl (3×30 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography using a gradient elution of 30-100% ethyl acetate in hexanes to afford the title compound as an oil (0.75 g, 54% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 50 ml of ethanol was dissolved 1.6 g of p-(1-imidazolyl)phenol and 1.4 g of anhydrous potassium carbonate was added to the solution. While stirring, 2.1 g of ethyl α-bromoisobutyrate was dropwise added to the mixture. Thereafter stirring was continued for 20 hours under reflux. After cooling to room temperature, the solvent was removed from the reaction mixture in vaccuo. The residue was dissolved in methylene chloride. After the solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water and a saturated aqueous sodium chloride solution, the solution was dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted out using chloroform-methanol (9:1) as an eluant. The solvent was removed from the eluate under reduced pressure to give the desired product, ethyl 2-[p-(1-imidazolyl)phenoxy]-2-methylpropionate, as an oily substance. ##STR80##
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:3]=[C:4]1[N:8]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: N#CN=C1NCCS1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CN=C1SCCN1Cc1ccc(Cl)cc1
Yield: 82.9 %

Procedure:
3,82 g (30 moles) of 2-cyanimino-thiazolidine, 4.9 g (30 mmoles) of 4-chlorobenzyl chloride and 4.3 g of anhydrous potassium carbonate are boiled in 100 ml of acetone for 5 hours. The inorganic salt is filtered off and the acetonic solution is evaporated. The residue is crystallized from 40 ml of isopropanol to yield 6.26 g (83%) of 2-cyanimino-3(4-chlorobenzyl)-thiazolidine, melting at 131° to 133° C. The product is isolated by filtration.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Product: Fc1cccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)c1

Procedure:
The title compound was prepared from the product of Example 105A and 3-fluorophenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 330.0 (M+H)+, retention time 1.55 minutes.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29][CH3:30])(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(O)=[O:32].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:24])[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C(C)C
Reaction time: 1 h
Yield: 57 %

Procedure:
3-Butyryl-4-(2-isopropylphenylamino)-8-(2-methylthioethoxy)quinoline (0.22 g, 0.52 mmol) was dissolved in methylene chloride (15 ml) and added to a mixture of 0.093g NaHCO3 in 15 ml H2O. A solution of 71% m-CPBA (0.12 g, 0.50 mmol) in 7 ml methylene chloride was added dropwise at 4° C. The solution was stirred for one hour at this temperature. The reaction mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. Chromatography with methylene chloride:methanol 10:1 as eluent gave 0.130 g (57%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](N)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[I:22]I.N(OCCC(C)C)=O>[Cu]I.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11]([I:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: II
Reactant: Nc1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: COCCOC
Product: Fc1ccc(-c2ncc(I)nc2-c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 5,6-bis(4-fluorophenyl)pyrazin-2-amine (1 g, 3.53 mmol, 1.00 equiv), ethylene glycol dimethyl ether (50 mL), I2 (450 mg, 1.78 mmol, 0.50 equiv), CuI (200 mg, 1.05 mmol, 0.30 equiv), and isoamyl nitrite (2.75 g, 10.87 mmol, 3.08 equiv) was stirred for 10 min at room temperature, then for an additional 2 h at 60° C. in an oil bath. The resulting mixture was concentrated in vacuo, and purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:40)) resulting in 1 g (72%) of 2,3-bis(4-fluorophenyl)-5-iodopyrazine as brown oil.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[N:31]1([CH2:36][C:37]([N:39]2[CH2:43][C:42](=O)[CH2:41][C@H:40]2[C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)=[CH:50][CH:49]=2)=[O:46])=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1>CS(C)=O>[N:31]1([CH2:36][C:37]([N:39]2[CH2:43][C:42](=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[CH2:41][C@H:40]2[C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)=[CH:50][CH:49]=2)=[O:46])=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: Fc1ccc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CC(=Cc2ccc(F)cc2)CN1C(=O)Cn1cncn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 10.8 %

Procedure:
Step (b) 4-Fluorobenzyl triphenylphosphine chloride (1 g, 2.46 mmol) in DMSO (2 mL) was added to a flask charged with sodium hydride (60% dispersion in oil, 124 mg, 3.10 mmol) and DMSO (2 mL). The reaction mixture was stirred at 70° C. for 3 hours and then (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-oxopyrrolidine-2-carboxamide (0.11 g, 0.25 mmol) in DMSO (2 mL) was added. The mixture was stirred for 16 hours at 70° C. and then quenched with saturated ammonium chloride (aq., 10 mL). This mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL). Product was purified from the mixture directly by column chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give with (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzylidene)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (15 mg, 0.027 mmol, 11% yield) as an oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=[O:7].C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6]([Cl:1])=[O:7]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 188.6 %

Procedure:
To a solution of 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (2.0 g) in thionyl chloride (20 ml) was added toluene (20 ml), the solution was stirred for 30 minutes at 100° C., then the reaction solution was concentrated in vacuo to provide 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (2.0 g). To a solution of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (253 mg) in dichloromethane (8 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (4 ml) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (400 mg), and the solution was stirred overnight at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting 3-fluoro-N-[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (423 mg) according to an analogous synthetic method to Example 337 described below, the title compound (418 mg) was obtained.
Reaction SMILES: [CH2:1](N(CC=C)C(=O)C)/[CH:2]=[CH:3]/[CH:4]=[CH2:5]>C1(C)C(C)=CC=CC=1>[CH3:1][CH:2]=[CH:3][CH2:4][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=C/C=C/CN(CC=C)C(C)=O
Solvent: Cc1ccccc1C
Product: CC=CCCCCCC

Procedure:
Dissolve 33.1 g (0.2 mol) of N-[(E)-2,4-pentadienyl]-N-(2-propenyl)-acetamide (title compound from Example A.3.) in 200 ml of xylene, pass a powerful stream of nitrogen through for 15 min, add 0.1 g of 4-hydroxyanisole, and then heat to reflux overnight. Concentrate, distil under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[C:18](Cl)=[O:19])[CH:9]=[CH2:10]>>[C:2]1([NH:1][C:18]([CH:12]2[CH2:13][CH:14]3[CH2:17][C:11]2([CH2:8][CH:9]=[CH2:10])[CH:16]=[CH:15]3)=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Product: C=CCC12C=CC(CC1C(=O)Nc1ccccc1)C2

Procedure:
20.5 g of aniline and 39.3 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are reacted in accordance with process A, affording 40.6 g (80.3% of theory) of a brown resin which is solid at room temperature and has a softening point of 66° C. The IR spectrum shows a band at 3300 cm-1 (--NH--) und at 1660 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)[CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccncc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccncc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.185 g, 0.5 mmol) and commercially available 4-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.06 g, 29%). MS (ISP) 413.0 [(M+H)+]; mp 193° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])C.Cl[C:36]1[N:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][N:37]=1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:36]3[N:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][N:37]=3)[CH:12]=2)[N:7]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: CCCc1cnc(Cl)nc1
Product: CCCc1cnc(-c2ccc3c(c2)c(Cl)c(C(=O)O)n3-c2ccc(OC(C)C)cc2)nc1

Procedure:
The title compound was prepared in accordance with Example 35, Method 1, step (d) from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (c)) and 2-chloro-5-propylpyrimidine, followed by ester hydrolysis in accordance with Example 1(c).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C1N(Cc2ccccc2)C(=O)C2(CCNCC2)N1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Combine 3,8-dibenzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (10 mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add in dropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm to ambient temperature and maintain for 1 h. Extract using saturated NaHCO3 (120 mL). Extract the aqueous phase using dichloromethane (120 mL). Combine the organic layers, extract with saturated NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Add anhydrous methanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo to obtain a residue and purify to obtain the title compound.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].O1CCCC1.[C:10]12[CH2:16][C:13](=[CH:14][CH:15]=1)[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]2=1.[OH-].[Na+]>O.[BH4-].[Na+]>[NH2:1][C:15]1[CH:14]=[C:13]2[CH2:16][C:10]=1[C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]2=1
Reactant: C1=C2CC(=C1)c1ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC1=C2CC(=C1)c1ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium azide (2 g) was combined with water (40 ml) and tetrahydrofuran (40 ml) and cooled to 0° C. Mercuric acetate (4g) was added to the cold solution and the mixture was stirred for 20 minutes. Benzobicyclo[2.2.1]heptadiene (2 g) was added to the stirred mixture and the resulting mixture was heated to 75° C. for 24 hours. The solution was cooled to room temperature, treated with 10% sodium hydroxide in water (10 ml) and sodium borohydride (0.4 g), and stirred for 1 hour. The two layers were separated and the organic layer was dried over magnesium sulfate and the solvent removed on a rotary evaporator. The residue was combined with tetrahydrofuran (20 ml) and added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 3 hours, treated with water (1 ml) and filtered. The solvent was removed on a rotary evaporator to provide the product as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]2[C:15]=1[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]2[CH2:19][CH:20]([CH3:22])[CH3:21].[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]2[C:15]=1[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]2[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCCO)n(Cc3cccc4ccccc34)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CCCCCO)n(Cc3cccc4ccccc34)cc21

Procedure:
The compound of Example 13, 5-(5-hydroxypent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (75 mg) was suspended in ethanol (50 ml). A suspension of 10% palladium on carbon (7 mg) in ethanol (3 ml) was added and the mixture was hydrogenated. When hydrogen uptake ceased, the reaction mixture was filtered and the solvent was removed by rotary evaporation. The crude product was purified by chromatography on silica eluting with ethyl acetate:isohexane (3:1) to give the title compound (29 mg) as an oil.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].Cl.[F:14][CH:15]([CH3:25])[C:16](=O)[CH:17]([CH3:23])[C:18](OCC)=[O:19]>CO>[F:14][CH:15]([C:16]1[N:12]=[CH:10][NH:11][C:18](=[O:19])[C:17]=1[CH3:23])[CH3:25]
Reactant: CCOC(=O)C(C)C(=O)C(C)F
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C(C)F)nc[nH]c1=O
Temperature: 64 °C
Yield: 59.4 %

Procedure:
To a solution in which 2.09 g of ethyl 4-fluoro-2-methyl-3-oxopentanoate had been dissolved in 20 ml of methanol were added 4.59 g of a 28 % sodium methoxide methanol solution and 1.61 g of formamidine acetate, and the mixture was stirred under reflux (64° C.) for 3 hours. Then, the reaction mixture was cooled to 10° C. or lower, 2.5 g of conc. hydrochloric acid was added to the mixture and the resulting mixture was concentrated under reduced pressure. To the concentrated solution was added 50 ml of acetone, and the mixture was stirred at 60° C. for 10 minutes, and then insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the concentrated solution was recrystallized from 10 ml of acetone to obtain 1.10 g of 6-(1-fluoroethyl)-5-methyl-4-pyrimidone (isolated yield: 59.2%).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.C1(N)C=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 1,4-phenylenediamine as the aniline component. (25%, MS=471.2 (M+H))
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:25])[O:20]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])O)[CH:5]=[CH:4][CH:3]=1.Cl.C(N(C(C)C)CC)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[O:25][C:19](=[O:20])[NH:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)n1)[C@H](O)c1ccccc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N[C@H](c2cccc(Br)n2)[C@@H](c2ccccc2F)O1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
To a solution of optically-enriched tert-butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-(2-fluorophenyl)-2-hydroxyethylcarbamate (375 mg, 0.912 mmol) in dichloromethane (4 mL) at room temperature was added hydrogen chloride (4M in dioxane, 3 mL, 12 mmol). After 15 min at room temperature, the reaction was warmed to 45° C. and held at that temperature for 15 min. The reaction was cooled and concentrated. The reaction was concentrated twice more from tetrahydrofuran. The resulting residue was suspended in tetrahydrofuran (10 mL), cooled to 0° C., and treated with diisopropylethylamine (0.319 mL, 1.82 mmol) and carbonyldiimidazole (222 mg, 1.368 mmol). After 5 min, the ice bath was removed and stirring continued for 3 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was suspended in dichloromethane, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% EtOAc/Hex) gave 75 mg. 1H NMR (CDCl3) δ: 7.60-7.68 (m, 1H), 7.46-7.56 (m, 2H), 7.35-7.45 (m, 2H), 7.24 (td, J=7.7, 1.0 Hz, 1H), 7.12 (ddd, J=10.3, 8.3, 1.0 Hz, 1H), 7.03 (s, 1H), 5.80 (d, J=5.3 Hz, 1H), 4.93 (d, J=5.3 Hz, 1H). 13C NMR (CDCl3) δ: 160.9, 158.9, 158.4, 142.0, 139.2, 130.5, 127.8, 127.2, 125.0, 124.3, 119.6, 115.6, 78.5, 63.1. 19F NMR (CDCl3) δ: −121.48-113.54 (m, 1F). Mass spec.: 337.1 (MH)+.