Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCCCCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was reacted with methanesulfonyl chloride (310 μL, 3.85 nmmol) to provide 0.43 g of N-{8-[4-amino-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide as an off white powder, m.p. 153-155° C. Analysis: Calculated for C19H27N5O2S: %C, 58.59; %H, 6.99; %N, 17.98; %S, 8.23; Found: %C, 58.40; %H, 6.99; %N, 17.71; %S, 8.14.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38](Br)[CH2:39][CH3:40]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:40][CH2:39][CH2:38][CH:21]4[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CCCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 3-[1-(t-butoxycarbonyl)piperidin-4-yl)]propyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH2:6]([S:8]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-])=[O:17])=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:7].[OH-].[Na+]>O>[CH2:6]([S:8]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:3])=[O:17])=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCS(=O)(=O)Nc1ccc(C(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
To 100 mL of thionyl chloride at 0° C. is added 25.1 g (0.1 mol) of 4-[(ethylsulfonyl)amino]benzoic acid sodium salt (prepared from the acid and sodium hydroxide in water and evaporation of solvent) under a nitrogen atmosphere. Reflux the reaction mixture for 24-40 hr. then remove the excess thionyl chloride in vacuo. Dissolve the crude material in tetrahydrofuran, filter through celite and evaporate the solvent to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:36])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][CH:34]=[N:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.N1C=CN=C1.[CH3:42][C:43]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])[CH3:44]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:36])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][CH:34]=[N:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([O:17][Si:46]([C:43]([CH3:45])([CH3:44])[CH3:42])([CH3:48])[CH3:47])[CH:16]=3)[C:3]=12
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (260 mg, 0.519 mmol) in dry DMF (10 ml), IMIDAZOLE (0.137 ml, 2.078 mmol) and TBDMSCl (0.270 ml, 1.558 mmol) were added and the solution stirred overnight. DMF was removed and residue was dissolved in DCM (50 mL) was washed with 0.5 N HCl aqueous solution. Organic phase was dried and solvent was removed. Crude was purified by silica gel flash chromatography (SNAP 25 g DCM:EtOH from 100:0 to 95:5) affording 3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (210 mg, 0.342 mmol, 65.8% yield) as a yellow pale solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH:30]=[CH2:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and allyl bromide (33 uL, 0.38 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 21 as a colorless oil (15 mg).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH:8][CH2:9][CH:10]=[CH2:11])=[O:7])(=O)[CH3:2].O=P(Cl)(Cl)Cl.Cl.[OH-].[Na+]>O>[CH3:2][C:1]1[O:7][C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:5][N:4]=1
Reactant: C=CCNC(=O)NNC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCNc1nnc(C)o1

Procedure:
1-Acetyl-4-n-propyl semicarbazide (35 g, 0.22 mol) prepared by method (a) above, was refluxed with POCl3 (150 ml) for 2 hours, until no more HCl was evolved. Excess POCl3 was taken off by a water pump and the mixture poured into 200 ml. iced water and neutralized with 50% NaOH to pH 7. Red oil was extracted with dichloromethane (2×180 ml), dried, filtered and evaporated down to yield an oil which was distilled in a vigreux flask to yield the title compound as a pink liquid which crystallised upon standing to a solid. (m.p. 46.5°-47.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH:5]=[O:6].C(O)C.[BH4-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18]
Reactant: O=Cc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of Example 287a (3.76 g, 12 mmol) in the mixture of ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.136 g, 3.60 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (3.72 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:6][CH:7]=1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>O>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:6]=[CH:7][C:2]([CH:17]=[O:16])=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: Fc1ccccc1Oc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2F)nc1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a mixture of 5-bromo-2-(2-fluoro-phenoxy)-pyridine (500 mg, 1.9 mmol) described in Manufacturing Example 74-1-1 and tetrahydrofuran (7 mL) was added n-butyl lithium (1.7 mL, 1.5 M n-hexane solution, 2.6 mmol) under nitrogen atmosphere at −78° C. N,N-dimethylformamide (0.29 mL, 3.7 mmol) was added to the reaction mixture at the same temperature, and the temperature was then gradually raised to 0° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (210 mg, 53%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][CH2:15][C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][CH2:15][C:16]1[O:20][C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:18][CH:17]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COCc1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COCc1ccc(C=C2N=C(c3cccs3)OC2=O)o1
Temperature: 90 °C
Yield: 50.7 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 5-(methoxymethyl)-2-furancarboxaldehyde (46 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 44 mg of the above-captioned compound.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CCO>[F:11][C:10]([F:12])([F:13])[CH2:9][N:8]([CH2:14][C:15]([F:16])([F:18])[F:17])[C:6]([C:5]1[CH:19]=[CH:20][C:2]([NH:24][CH2:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=1)=[O:7]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (200 mg, 0.574 mmol) and tert-butyl (2S)-2-(aminomethyl)piperidine-1-carboxylate (150 mg, 0.689 mmol) in 10 mL of EtOH containing TEA (0.120 mL, 0.861 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent Yield: 311 mg (99%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.47 (s, 9H), 1.52 (m, 1H), 1.66 (m, 1H), 1.71 (s, 2H), 1.74 (s, 2H), 2.79 (m, 1H), 3.36 (m, 1H), 3.65 (m, 1H), 4.09 (s, 1H), 4.26 (q, J=8.33 Hz, 4H), 4.64 (m, 1H), 7.07 (d, J=8.98 Hz, 1H), 7.55 (dd, J=8.89, 2.05 Hz, 1H), 8.30 (d, J=2.15 Hz, 1H), 8.39 (m, 1H); MS (ESI) 542.81 (MH+).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:15]([Cl:24])[CH:14]=2)=[C:10]([CH3:12])[N:11]=1>CN(C)C=O>[Cl:24][C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[C:17]([Cl:19])[C:16]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1cc(Cl)c(S(N)(=O)=O)c(Cl)c1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1

Procedure:
Ethyl isocyanate (0.015 ml, 0.19 mmol) is added to a stirred solution of 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide (Example 26) (0.043 g, 0.127 mmol) in dry dimethylformamide (1.0 ml) under argon. After heating at 85° C. for 3 hours more ethyl isocyanate (0.015 ml, 0.19 mmol) is added and heating continued for a further hour. The reaction is concentrated in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate—hexane (1:1 increasing to 4:1) to give the title compound. MH+ (TOF, MS, ES+): 408.9, 410.9, 412.8
Reaction SMILES: [ClH:1].COC1C=C2C(=CC=1OC)C([CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])C2.COC1C=C2C(=CC=1OC)C(CNC)C2.[CH3:51][O:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][C:61]=1[O:62][CH3:63])[CH2:58][CH:57]([CH2:64]CNC)[CH2:56]2>>[ClH:1].[CH3:63][O:62][C:61]1[CH:60]=[C:59]2[C:55](=[CH:54][C:53]=1[O:52][CH3:51])[CH2:56][CH:57]([CH2:64][CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:58]2
Reactant: CNCCC1Cc2cc(OC)c(OC)cc2C1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Agent: CNCC1Cc2cc(OC)c(OC)cc21
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CCC1Cc3cc(OC)c(OC)cc3C1)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by [2-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)ethyl]methylamine.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[CH:15](O)=O>>[CH2:1]([N:5]1[C:10]2[N:11]=[CH:15][NH:12][C:9]=2[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of 36.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) in 100 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 42.9 g (not dried). (XI). The amide (XI) was refluxed in 100 ml of 2 N NaOH for 2 hours and then neutralized with 5 N HCl. The crystals were filtered off and washed with ethanol. Yield 28.4 g (74%) (XII), NMR. ##STR8##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][NH:11][C:4]1[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=[C:2]([C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=2)[CH:3]=1
Reactant: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COCc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 0.58 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [266 mg, 1.28 mmol, see Example 49(b) step 2], Cs2CO3 (1.56 g, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (69 mg, 0.06 mmol) in ethylene glycol dimethyl ether (4 mL) and water (1 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 16 hours the mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxymethyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [165 mg, 60%, Example 85] as a solid. LCMS RT=2.59 minutes, MS: 474 (M+H). IC50=2.7 nM
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:38][O:39][CH2:40][C:41]#[CH:42]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:42]#[C:41][CH2:40][O:39][CH3:38])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CCOC
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 3-methoxypropyne (350 mg, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (40 mg), and copper(I) iodide (20 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed with toluene (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (1/3 to 1/2 ethyl acetate/hexane) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxy-prop-1-ynyl)-pyrazin-2-yl]-propionamide (330 mg, 69.5%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H26ClN3O4S (M+H)+ 476.1406, found 476.1405.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[CH2:34]([N:38]1[C:46]2[N:45]=[C:44]([Cl:47])[NH:43][C:42]=2[C:41](=[O:48])[N:40]([CH2:49][CH2:50][CH2:51]/[C:52](=[N:55]/[H])/[NH:53]O)[C:39]1=[O:57])[CH2:35][CH2:36][CH3:37]>CN1CCCC1=O>[CH2:34]([N:38]1[C:46]2[N:45]=[C:44]([Cl:47])[NH:43][C:42]=2[C:41](=[O:48])[N:40]([CH2:49][CH2:50][CH2:51][C:52]2[N:53]=[C:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[O:11][N:55]=2)[C:39]1=[O:57])[CH2:35][CH2:36][CH3:37]
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3cccc(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.2 %

Procedure:
(3-Chlorophenyl)acetic acid (0.1 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol) and 1H-1,2,3-benzotriazol-1-ol (15 mg, 0.11 mmol) were stirred in 1-methyl-2-pyrrolidinone (1 ml). To this was added (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (34 mg, 0.1 mmol) and the mixture stirred at rt for 17 h and then at 80° C. for 24 h. The reaction mixture was purified, without further modification, by preparative HPLC (auto prep) to give the title compound (13 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13]S(C)=O.[H-].[Na+]>O>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Clc1ccc2ccncc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1nccc2ccc(Cl)c(Cl)c12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
7,8-Dichloroisoquinoline (0.019 mole) in 100 ml. of dimethylsulfoxide is added to a solution of sodium hydride (0.11 mole) in 100 ml. of dimethylsulfoxide at 70° C. The reaction mixture is stirred at 70° C. for 4 hours under a nitrogen atmosphere. The reaction mixture is cooled, 100 ml. of water is added, and the mixture is poured into 1500 ml. of water. The aqueous mixture is extracted with benzene. The extract is washed, dried over sodium sulfate and evaporated to give 7,8-dichloro-1-methylisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[Cl:44][C:45]1[CH:46]=[C:47]([N:52]=[C:53]=[O:54])[CH:48]=[CH:49][C:50]=1[Cl:51]>C1(C)C=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:53]([NH:52][C:47]4[CH:48]=[CH:49][C:50]([Cl:51])=[C:45]([Cl:44])[CH:46]=4)=[O:54])=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 24 h

Procedure:
To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (600 mg, 1.3 mmol) in toluene (20 mL) were added ethyldiisopropylamine (0.454 mL, 2.6 mmol) and 3,4-dichlorophenylisocyanate (270 mg, 1.4 mmol), and the resulting solution was stirred for 1 day under reflux. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), and then recrystallized from ethyl acetate to thereby yield 280 mg of the title compound.