Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1([C:15]2[N:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:18][C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O.ClCCl>C(Cl)(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:17]1[NH:18][C:19](=[O:21])[C:20]([Cl:1])=[C:15]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:16]=1)[CH3:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
1.87 g of N-chlorosuccinimide are added to a solution of 3.75 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate described in example 6a (step (2′a)a) in 50 ml of chloroform. The reaction medium is stirred at ambient temperature for 2 hours. 20 ml of water and 50 ml of dichloromethane are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 99/01 then 98/02 then 97/03 dichloromethane/methanol, so as to give 2.81 g of (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.O.C(OCC)(=O)C.CC#N>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])[C:9](=[O:18])[C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Nc1cccc(Br)c1)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(C(=O)c1c(F)cccc1F)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-bromophenyl)-2,6-difluorobenzamide in 200 mL of DMF at room temperature and under nitrogen atmosphere, NaH 60% in oil dispersion (104.7 mmol) is slowly added and the reaction mixture is stirred for 30 minutes. Tert-butylbromoacetate (104.7 mmol) is added and the reaction stirred at room temperature. After 12 hours the reaction is complete by TLC (hexanes:ethyl acetate=8:2) and analytical LCMS (20 to 100% CH3CN). Ethyl acetate and water are added to the reaction mixture and the phases are separated. The organic phase is dried on sodium sulfate, filtered and the solvent is evaporated. The crude is purified by automated column chromatography (gradient of hexanes and ethyl acetate) to give tert-butyl 2-(N-(3-bromophenyl)-2,6-difluorobenzamido)acetate: 1H NMR (400 MHz, CDCl3) δ 7.36 (bs, 1H), 7.20 (m, 1H), 7.07 (m, 2H), 6.96 (t, J=8 Hz, 1H), 6.62 (td, J=8 Hz, J2=1.2 Hz), 4.32 (s, 2H), 1.39 (s, 9H); MS: (ES+) 448.0 (M+23)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:27][C:26]=1[F:36].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][C@@H:9]1[C:21](=[O:22])[NH:24][C:25]1[CH:35]=[CH:34][C:28]([C:29](=[O:30])[N:31]([CH3:32])[CH3:33])=[CH:27][C:26]=1[F:36])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(=O)c1ccc(N)c(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc(NC(=O)[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Yield: 17.9 %

Procedure:
Into a solution of 2 (1.25 g, 3.61 mmol) in CHCl3 (25 mL) was added 5 (0.66 g, 3.61 mmol), EEDQ (1.07 g, 4.32 mmol), and triethylamine (0.74 mL, 5.33 mmol). The solution was stirred at reflux for 19 h before cooling to RT and adding EtOAc. The solution was washed sequentially with 1N HCl, 0.1N NaOH, water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was purified on a silica gel column eluted with 20% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions. to give 6 (0.33 g, 18%). MS: APCI (AP+): 510.3 (M)+, (AP−): 508.4 (M)−.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[NH:16][C:15](=[O:17])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])#[N:2].C(=O)([O-])O.[Na+].Cl>CO.O.[Pd]>[NH2:2][CH:1]1[N:16]2[C:15](=[O:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]2[C:4]2[S:5][CH:6]=[CH:7][C:3]1=2
Reactant: N#Cc1ccsc1-c1[nH]c(=O)c(-c2ccccc2)cc1C(=O)O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: NC1c2ccsc2-c2c(C(=O)O)cc(-c3ccccc3)c(=O)n21
Reaction time: 0.75 h
Yield: 100.5 %

Procedure:
A suspension of 45.4 g of 2-(3-cyano-2-thienyl)-1,6-dihydro-6-oxo-5-phenylnicotinic acid in 850 ml of methanol was treated with a solution of 59.2 g of sodium hydrogen carbonate in 280 ml of water, whereupon the mixture was stirred for 45 minutes. 2.27 g of 10 percent palladium/carbon were then added thereto and the mixture was hydrogenated at room temperature. After completion of the reaction the mixture was acidified with 400 ml of 2N hydrochloric acid, the catalyst was filtered off and the filtrate was concentrated in a vacuum. After the addition of 400 ml of water, crystals separate. After stirring overnight, the mixture was suction filtered and the yellow crystals were dried. There was obtained in quantitative yield 45.9 g of 4-amino-4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]pyrrolo[1,2-a]pyridine-9-carboxylic acid with a m.p. of 227°-235°.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:10])/[C:6](=[CH:8]/[CH3:9])/[CH3:7].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(=S)=S.CCCCCC.O>[CH3:7][CH:6]1[CH:8]([CH3:9])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1=[O:10]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCCCCC
Solvent: O
Product: CC1C(=O)c2ccccc2C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Aluminum trichloride in an amount of 30.7 g (250 mmol) was suspended in 150 mL of dried carbon disulfide (dried and distilled on calcium hydride) and was brought to an ice-cooling temperature. Then, 25.1 g (212 mmol) of tigloyl chloride was mixed with 16.6 g (212 mmol) of benzene, and to the resultant mixture was added dropwise the above-produced carbon disulfide solution, followed by continuous stirring at room temperature. As the result, a yellow solution was gradually produced. The solution was allowed to stand overnight, with the result that the solution was separated into two phases including a brown phase and a colorless phase. The solution was allowed to react for another 5 hours under refluxing. The resultant reaction mixture was brought back to room temperature and thereafter, was poured onto the mixture of 250 g of water and 250 mL of concentrated hydrochloric acid, followed by stirring for about one hour. Then, the resultant product was subjected to extraction and separation four times repeatedly with 200 mL each of ether. The ether phases thus produced were combined together, and dried with calcium chloride anhydride as the drying agent. After filtering away the used drying agent, the ether was distilled away and the brown viscous oil was obtained. Because of its being readily soluble in hexane, the oil was again dissolved in hexane, and the resultant solution was washed twice with 150 mL each of saturated aqueous solution of sodium carbonate and twice with 150 mL each of saturated aqueous solution of sodium chloride, and dried with magnesium sulfate anhydride. By distilling away the hexane, there was obtained 19.9 g of 2,3-dimethylindane-1-one.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.CN.CO.CC(O)=O.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cnc2ccccc2c1
Yield: 48.2 %

Procedure:
A solution of 3-quinolinecarboxaldehyde (1.5 g, 10 mmole), 2.0 M CH3NH2/MeOH (10 mL, 20 mmole), glacial AcOH (0.6 mL, 10 mmole), and NaBH3CN (0.35 g, 11 mmole) in MeOH (20 mL) was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (10% MeOH/CH2Cl2) gave the title compound (0.83 g, 24%) as a slightly yellow viscous oil: MS (ES) m/e 173 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([C:80]2[CH:81]=[C:82]3[CH:88]=[CH:87][N:86]([CH3:89])[C:83]3=[N:84][CH:85]=2)[C:34]([C:36]2[CH:37]=[C:38]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53](=[O:60])[N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)=[CH:47][C:46]=3[C:61]([N:63]3[C@H:72]([CH2:73][N:74]4[CH2:79][CH2:78][O:77][CH2:76][CH2:75]4)[CH2:71][C:70]4[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=4)[CH2:64]3)=[O:62])[N:39]3[C:44]=2[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:35])=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O1CCCC1>[OH:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]([C:80]2[CH:81]=[C:82]3[CH:88]=[CH:87][N:86]([CH3:89])[C:83]3=[N:84][CH:85]=2)[C:34]([C:36]2[CH:37]=[C:38]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53](=[O:60])[N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)=[CH:47][C:46]=3[C:61]([N:63]3[C@H:72]([CH2:73][N:74]4[CH2:75][CH2:76][O:77][CH2:78][CH2:79]4)[CH2:71][C:70]4[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=4)[CH2:64]3)=[O:62])[N:39]3[C:44]=2[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:35])=[CH:31][CH:32]=1
Reactant: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O)cc3)cnc21
Reaction time: 0.08 h

Procedure:
A 1M solution of tetrabutylammonium fluoride (3.14 mL, 3 mmol) in tetrahydrofuran is added at ambient temperature to a solution, in 30 mL of tetrahydrofuran, of the compound obtained in Step E (2.92 g, 2.9 mmol). After stirring for 5 minutes, the reaction mixture is poured into a 50/50 mixture of ethyl acetate and saturated aqueous NaHCO3 solution. The separated organic phase is washed with water and then with brine. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel (dichloromethane/ethanol/ammonia gradient) to yield the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2Cl)[C:16]([OH:21])=[N:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:2][C@@H:3]1[CH2:4][CH2:5][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:21])[NH:15][CH:14]=[CH:13]3)[CH2:7][CH2:8]1
Reactant: N[C@H]1CC[C@@H](Oc2cc3ccnc(O)c3cc2Cl)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 25 °C

Procedure:
150 mg (0.46 mmol) of 6-cis-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one hydrochloride (10) were dissolved in 10 ml of methanol. After addition of molecular sieves 4 A, 92.3 mg (0.57 mmol) of triethyl amine, 273.8 mg (4.56 mmol) of acetic acid and 0.57 mmol of the corresponding aldehyde, a solution of 86.0 mg (1.37 mmol) of sodium cyanoboro hydride is added dropwise and the mixture is stirred at room temperature until complete conversion is achieved. In some cases it was necessary to heat the mixture to 70° C. to achieve complete conversion. For the isolation of the products the solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with 1 N NaOH and sat. sodium chloride solution, dried with magnesium sulfate and evaporated. The mono- or bis alkylated products, if obtained, were purified by preparative HPLC or precipitated from methanolic HCl
Reaction SMILES: [Cl-].C(C[P+](C)(C)C)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=1.[F:28][C:29]1([F:57])[CH2:34][CH2:33][N:32]([C:35]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH:54]([CH3:56])[CH3:55])[CH2:50][CH2:49]2)=[O:47])=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:57][C:29]1([F:28])[CH2:34][CH2:33][N:32]([C:35]([C:37]2[N:38]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)[C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([C:46]([N:48]2[CH2:49][CH2:50][N:51]([CH:54]([CH3:55])[CH3:56])[CH2:52][CH2:53]2)=[O:47])=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH2:30]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OCc1ccc(F)cc1
Agent: C[P+](C)(C)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3Cc2ccc(F)cc2)CC1

Procedure:
The title compound was synthesized in analogy to example 74, from (cyanomethyl)trimethylphosphonium chloride (prepared according to Tetrahedron Lett. 1996, 37 (14), 2459-62), potassium bis(trimethylsilyl)amide, 4-fluorobenzylalcohol and (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32) in toluene to give the compound as a colorless foam (37%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:19]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)CCCCCl)c1ccc(Cl)cc1

Procedure:
1-(4-Chlorophenyl)-1-methylethylamine hydrochloride (4.0 g) was reacted with 5-chloropentanoyl chloride (3.0 g) in dichloromethane (15 ml) containing triethylamine (8.1 ml) in a similar manner to Example 52b, to give 5-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]pentanamide.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[S:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:43][C:40]([F:41])([F:42])[C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[S:10][CH:11]=[C:7]([CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[N:8]=4)=[CH:13][CH:14]=3)[N:28]=2)=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(-c2nc(Cn3ccnn3)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(-c4nc(Cn5ccnn5)cs4)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A mixture of 0.129 g (0.50 mmol) 4-(4-[1,2,3]triazol-1-ylmethyl-thiazol-2-yl)-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.144 g (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 248 mg raw material which was purified on silica. Elution with ethyl acetate yielded 122 mg white crystals that gave, after recrystallisation from 6 ml ethanol, 79 mg (31%) pure 1-[2-(4-{2-[2-((E)-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-thiazol-4-ylmethyl]-1H-[1,2,3]triazole melting at 163-165° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:3]1=[O:24].[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:47][CH2:46][N:45]3[C:38](=[CH:39][C:40]4[CH2:41][C:42]([CH3:49])([CH3:48])[CH2:43][C:44]=43)[C:37]2=[O:50])=[CH:34][C:33]([F:51])=[CH:32][C:31]=1Br)(=[O:27])[CH3:26].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(OCC)C.O.C(OCC)(=O)C>[F:51][C:33]1[CH:32]=[C:31]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[C:3](=[O:24])[N:2]([CH3:1])[CH:7]=2)[C:30]([CH2:29][O:28][C:25](=[O:27])[CH3:26])=[C:35]([N:36]2[CH2:47][CH2:46][N:45]3[C:38](=[CH:39][C:40]4[CH2:41][C:42]([CH3:48])([CH3:49])[CH2:43][C:44]=43)[C:37]2=[O:50])[CH:34]=1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccncn2)c1=O
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: CO
Solvent: CCOCC
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccncn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 130 °C
Yield: 37.7 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 109c (170 mg, 0.5 mmol), 189a (150 mg, 0.33 mmol), 1,2-dimethoxyethane (4 mL) and 1M aqueous sodium carbonate (1 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (19 mg, 0.02 mmol) was added. The mixture was heated in microwave to 130° C. for 10 min. After this time, Ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-60:35:5 methylene chloride:diethyl ether:methanol to afford a 37% yield (71 mg) of 189b.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([O:17][CH3:26])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-(1-Hydroxyphthalazin-6-yl)-4-methylbenzoic acid (2.71 g, 9.67 mmol) was suspended in methanol (96.7 mL), thionyl chloride (2.12 mL, 29.0 mmol) was added and the mixture was stirred at 50° C. for 1.5 h and at RT overnight. The mixture was concentrated to give the title compound. MS (ES+): 295(M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].BrCCCCC(OC)=O>>[CH:17]1[CH:18]=[CH:19][C:14]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]([OH:12])=[N:9][C:8]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: COC(=O)CCCCBr
Agent: [Na]
Product: O=C1N=C(O)NC1(c1ccccc1)c1ccccc1

Procedure:
Following the method of Cook et al, Res, Comm. Chem. Path, Pharm. 5:767(1973), sodium diphenylhydantoin is reacted with methyl 5-bromovalerate followed by acid hydrolysis to yield the following: ##STR19##
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.[CH:48]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49]1.C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:31]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:53][CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)=[NH:47])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: NC1CCCC1
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)NC2CCCC2)c1
Reaction time: 72 h
Yield: 77 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a solution of cyclopentylamine (255 mg., 3.0 mmoles, glacial acetic acid (0.3 ml., 5.3 mmoles) and chloroform (10 ml.). The mixture was held for 72 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (3 × 50 ml.), washed with saturated aqueous sodium chloride solution (3 × 50 ml.), dried (Na2 SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5ml.) and then evaporated in vacuo to an oil. The oil was crystallized from warm 1,2-dimethoxyethane [850 mg., 77% yield, Rf .30 (4:1, benzene:ethanol on silicic acid), m.p.--forms a gel at 78° C.].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4O)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O1CCCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:14][CH:15]4[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:19][CH2:18][CH:16]4[CH2:17]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CC(CO)C(c2ccccc2O)C1)C1(c2ccc(Cl)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N1CC2COc3ccccc3C2C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-[1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-(hydroxymethyl)pyrrolidin-3-yl]phenol (13.0 mg, 0.0000350 mol), triphenylphosphine (20.0 mg, 0.0000762 mol) and diisopropyl azodicarboxylate (15.0 μL, 0.0000762 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) was stirred at rt for 4 h. The mixture was diluted with methanol (0.80 mL) and the desired product from the mixture was isolated and purified by prep-HPLC. LCMS: m/z 354.5 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Nc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Nc1ccccc1
Yield: 22 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using aniline (12 mg, 0.13 mmol) as the coupling partner. Chromatography (10% methanol/dichloromethane) through SiO2 yielded 14 mg (22%) of the titled compound. ESI-MS m/z 367 (MH+), 365 (M−H−).