Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C@H:27]3[CH2:29][C@H:28]3[CH2:30][CH2:31]O)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C@H:27]3[CH2:29][C@H:28]3[CH2:30][CH2:31][O:8][C:6]3[CH:5]=[CH:4][C:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:2]([F:1])[CH:7]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (1.3 g, 4.61 mmol) in 15 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (1.02 g, 1.70 mmol) in 5 ml of anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 3.63 g, 10.5 mmol) and di-tert-butyl azodicarboxylate (2.13 g, 9.23 mmol). The mixture was stirred at RT for 3 hours, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel (Biotage 100 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (1500 ml) to afford the title compound. LC/MS (m/z) 448.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20]Br)[CH2:16][CH2:15]1)=[O:13]>CO.[OH-].[K+]>[CH:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][S:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=CN1CCC(CBr)CC1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCC1CCN(C=O)CC1
Reaction time: 20 h

Procedure:
To a solution of (A) (5.3 g, 0.03 mole) in methanol (10 ml), 5 N potassium hydroxide in methanol (5 ml) was added, followed by N-formyl-4-bromomethylpiperidine (5.2 g, 0.025 mole). The mixture was left at room temperature for 20 hours. After removal of the solvent in vacuo, the residue was diluted with ether (50 ml) and filtered. The filtrate was washed with two 5 ml portions of 2 N sodium hydroxide, followed by water and dried. The solvent was stripped in vacuo, and the residue was chromatographed on silica gel (100 g), eluting with ether to give (B) as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[B:21]1(B2OC(C)(C)C(C)(C)O2)[O:25]C(C)(C)C(C)(C)[O:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)=[CH:3][C:2]([B:21]([OH:25])[OH:22])=[N:7]1
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CN1CCn2nc(Nc3cc(B(O)O)nn(C)c3=O)cc2C1
Temperature: 50 °C

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 153a (200 mg, 0.68 mmol), bis(pinacolato)diboron (Pin2B2, 863 mg, 3.40 mmol), Pd2(dba)3 (55 mg, 0.060 mmol), X-Phos (60 mg, 0.12 mmol), potassium acetate (60 mg, 1.36 mmol), and 1,4-dioxane (10 mL). The system was evacuated and then refilled with N2. It was then heated at 50° C. for 2 h. After completion of the reaction, the mixture was filtered and the solid was washed with ethyl acetate (10 mL). The combined filtrate was evaporated under reduced pressure to afford 153b as a pale yellow solid, which was used in the next step. MS-ESI: [M+H]+ 305.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:16]2[N:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added isocyanatobenzene (19 mg, 0.16 mmol) at ambient temperature drop-wise. The reaction was stirred for 5 minutes then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a pale-yellowish solid (30 mg, 87% yield). MS (apci) m/z=435.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15].Cl.[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19].Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][C:6]2[C:7](=[O:14])[O:8][C:9]3[C:4]([C:5]=2[CH3:15])=[CH:3][C:2]([F:1])=[C:11]([OH:12])[C:10]=3[F:13])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(OC(=O)c2ccc(NC(=N)N)cc2)c(=O)oc2c(F)c(O)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a pale yellow solution of 6,8-difluoro-7-hydroxy-4-methylcoumarin (Compound 5, 0.13 g, 0.61 mmol) in THF (5 mL) under air at room temperature is added a solution of 4-guanidinobenzoic acid hydrochloride (132 mg, 0.61 mmol) in 4 mL water, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 125 mg, 0.65 mmol). The resulting solution is stirred at room temperature overnight, followed by the addition of more EDC (100 mg). After two hours, TLC analysis indicates the starting materials are consumed. Volatiles are removed in vacuo, and a portion of the residue (0.61 g of pale yellow powder) is purified by chromatography on SEPHADEX LH-20 resin using water:dioxane (1:1) as eluant to give nonfluorescent Compound 35 as a colorless powder: Rf =0.30 (MeCN:H2O:AcOH 90:5:5). Upon treatment with ammonia vapor, a TLC spot corresponding to Compound 35 becomes blue fluorescent.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Cl.[C:27]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), triethylamine (2.8 cc) and 4,4-diphenylpiperidine hydrochloride (2.7 in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 7 hours at this temperature. After purification by flash-chromatography on a silica 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (10 cc), 2-[3-(4,4-diphenylpiperidino)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 168° C.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH2:11]N)[OH:10]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[C:2]1([C:1]2[O:10][CH2:9][CH2:11][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: c1ccc(C2=NCCO2)cc1
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A mixture of about 104.1 grams (1.0 mole) benzonitrile, about 63.1 grams (1.03 mole) ethanolamine, and about 6.2 grams (0.025 mole) cadmium acetate dihydrate is heated and stirred at about 125 degrees C. to about 130 degrees C. under nitrogen for about two days. The product is distilled under vacuum and the fraction boiling at about 120 degrees C. to about 121 degrees C. at 16 mmHg is collected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 33.3 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.1 mg, 0.12 mmol) in dichloromethane (1 mL) was added ethanesulfonyl chloride (32 mg, 0.24 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 26.4 mg (33%) of the title compound as off white solid. MS (ES) m/e 661.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([N:19]([CH3:27])[CH2:20][C:21]2[O:22][C:23]([CH3:26])=[N:24][N:25]=2)[C:16]2[C:11](=[CH:12][C:13]([CH3:28])=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].COC1C=CC=CC=1C1N=C(NCC2OC(C)=NN=2)C2C(=CC(C)=CC=2)N=1.CI>CN(C=O)C>[CH3:28][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([N:19]([CH3:27])[CH2:20][C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)=[N:18][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])=[N:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccccc1-c1nc(N(C)Cc2nnc(C)o2)c2ccc(C)cc2n1
Agent: COc1ccccc1-c1nc(NCc2nnc(C)o2)c2ccc(C)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc2c(N(C)Cc3nnc(C)o3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine To a stirring suspension of freshly washed sodium hydride (42 mg, 1.04 mmol) in dry DMF at 0° C. under a nitrogen atmosphere was added the [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine (180 mg, 0.518 mmol, in 5 ml DMF). After 30 minutes at 0° C., MeI (74 μL, 1.19 mmol) was added and the reaction was allowed to warm to room temperature. After one hour the reaction was quenched with water and extracted 3 times with EtOAc. Organics were combined, dried over MgSO4, filtered and concentrated to a yellow oil. Purified by flash chromatography 50/50 EtOAc/hexanes to afford the desired product as a clear oil. 128 mg, 66% yield. LC/MS (10-99%) M/Z 376.1, retention time 2.06 minutes.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][CH:11](C3C=CC=CC=3C)[N:10]2[CH3:21])=[CH:5][C:4]=1[S:23](=[O:32])(=[O:31])[N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27].[C:33](O)(=O)[CH3:34]>>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:10][C:9]3[CH:6]=[CH:5][CH:4]=[CH:3][C:33]=3[CH3:34])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:23](=[O:31])(=[O:32])[N:24]([CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH3:30]
Reactant: CCCN(CCC)S(=O)(=O)c1cc(C2(O)CSC(c3ccccc3C)N2C)ccc1Cl
Reactant: CC(=O)O
Agent: Br
Product: CCCN(CCC)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3C)n2C)ccc1Cl

Procedure:
Obtained by a procedure analogous to that indicated in Example 1(b), from 4-(4-chloro-3-dipropylsulfamoylphenyl)-3-methyl-2-(2-methylphenyl)-thiazolidin-4-ol hydrobromide, by boiling in glacial acetic acid for 2 hours. The reaction mixture is concentrated, water is added to the residue and the crystals are filtered off. Melting point 218°-220° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: c1cn(-c2nc(NCCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=O)[CH3:2].Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].C[O-].[Na+].C(O)(=O)C>CO>[OH:6][CH2:7][CH2:8][C:4]1[C:5](=[O:9])[NH:14][C:11]([CH3:12])=[N:13][C:1]=1[CH3:2]
Reactant: CC(=O)C1CCOC1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(C)c(CCO)c(=O)[nH]1
Yield: 22.6 %

Procedure:
3-acetyldihydro-2(3H)-furanone (25.6 g) was added to a stirred mixture of acetamidine hydrochloride (20 g) and sodium methylate (110 g) in methanol (150 ml). The reaction mixture was stirred and refluxed overnight. The reaction mixture was cooled and acetic acid (36 g) was added dropwise. The precipitate was filtered off and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The crystals were filtered off and dried, yielding 7.6 g (22%) of 5-(2-hydroxyethyl)-2,6-dimethyl-4(3H)-pyrimidinone (intermediate 4).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=O)[NH2:7]>ClCCCl>[C:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])#[N:7]
Reactant: COCCOc1cc(C(N)=O)cc(C(=O)OC)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COCCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
POCl3 (20 mmol) was added to the solution of methyl 3-carbamoyl-5-(2-methoxyethoxy)benzoate (15 mmol) in 35 ml 1,2-dichloroethane and stirred for 5 h at reflux. Then the solution was cooled to room temperature, poured to the ice-water and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated to yield methyl 3-cyano-5-(2-methoxyethoxy)benzoate (90.5%).
Reaction SMILES: [O:1]=[C:2]([CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1>CN(C)P(N(C)C)(N(C)C)=O>[O:1]=[C:2]([CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CCCC(=O)CCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCC(=O)CCCC(C)(C)C)cc1

Procedure:
A solution of 15 g. (43.2 mmoles) 11-oxo-15,15-dimethylhexadecyl bromide and 14.3 g. (2 eq.) ethyl 4-aminobenzoate in 100 ml. hexamethylphosphoramide is heated at 120° C. for 18 hours. The cooled solution is diluted with 200 ml. water and filtered. The resultant solid is washed in portions with 200 ml. 50% ethanol-water, dried, and crystallized from ethanol to yield a colorless, waxy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-])=[O:2].[PH2]([O-])=O.[Na+]>O1CCCC1.CS(C)=O.O.[Pd]>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:4]([NH:1][OH:2])[CH:9]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Cl)cc1NO
Reaction time: 1 h
Yield: 110.3 %

Procedure:
Methyl (2-nitro-4-chlorophenyl)acetate (5.0 g, 21.7 mmol) was dissolved in 250 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide. To this was added 900 mg of 10% Pd/C. A solution of 5.38 g of sodium hypophosphite in 18 ml of water was added dropwise over a 40 minute period. After stirring for 4 hours another 2.68 g of sodium hypophosphite (in 8 ml of water) was added over a 10 minute period. After stirring for one hour the reaction mixture was filtered through Celite and the filtrate diluted with 500 ml of CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3 then brine and dried with Na2SO4. The solvents were evaporated under reduced pressure leaving 5.16 g of a yellow oil (110% of theory). NMR (300 MHz, CDCl3): 3.51 (2 H, s), 3.69 (3 H, s), 5.50 (1 H, br s), 6.88 (1 H, dd, J=1,8), 7.01 (1 H, d, J=8), 7.34 (1 H, d, J=1), 7.56 (1 H, br s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]=[N+:20]=[N-:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester and sodium azide in DMF was stirred at 60° C. overnight. The mixture was poured into water and the resulting mixture was extracted with EtOAc. The organic phase was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 7.9 (2H, d), 7.12 (2H, d), 4.79 (2H, d), 3.05 (3H, s), 2.58 9 (1H, t).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:19][S:20]SC>[Cu].N1C=CC=CC=1>[CH3:19][S:20][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: CSSC
Reactant: O=Cc1cc(Br)c(O)c(OCc2ccccc2)c1
Agent: [Cu]
Solvent: c1ccncc1
Product: CSc1cc(C=O)cc(OCc2ccccc2)c1O
Temperature: 95 °C
Yield: 75.6 %

Procedure:
In an alternative procedure a 50-L flask equipped with a mechanical stirrer was charged with 3-bromo-4-hydroxy-5-benzyloxybenzaldehyde (1.332 kg, 4.34 mol), Copper powder (1.068 kg, 16.82 mol), dimethyldisulfide (1.068 kg, 11.36 mol) and pyridine (23 L). The mixture was heated at 95° C. overnight with gentle stirring, filtered, and the filtered cake was washed with dichloromethane (30 L). The pyridine filtrate was distilled off to leave a black residue, from which the product was extracted with the dichloromethane washes. The combined organic extracts were washed with 2N HCl until it became light brown and the acidic aqueous layer was clear. The organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness. Crystallization from dichloromethane-hexane gave the title compound (900 g, 76%): mp 117°-119° C.; NMR (CDCl3) δ 2.50 (s, SCH3), 5.20 (s, OCH2Ar), 6.72 (s, OH), 7.34-7.46 (m, ArH), 9.78 (s, ArCHO)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1>>[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:2]([CH3:3])[CH3:1])=[O:10])=[CH:7][N:6]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNC
Product: CN(C)C(=O)c1ccc(Cl)nc1

Procedure:
The title compound (D36) was prepared from dimethylamine and 6-chloronicotinic acid according to the procedure described for Description 35. MS electrospray (+ve ion) 185 (MH+).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](B(O)O)=[CH:13][N:12]=1.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=[N:12][CH:13]=3)[C:7]1=2
Reactant: OB(O)c1cncc2ccccc12
Reactant: Brc1cccc2ccsc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc2c(-c3cccc4ccsc34)cncc2c1
Temperature: 90 °C
Yield: 6.1 %

Procedure:
A vessel capable of sealing was charged with a mixture of 7-bromobenzo[b]thiophene (430 mg, 2.018 mmol), isoquinolin-4-ylboronic acid (419 mg, 2.421 mmol), PdCl2(dppf)-CH2Cl2 adduct (82 mg, 0.101 mmol), dioxane (6 mL), and a 2.0 M aqueous solution of K3PO4 (3 mL, 1.41 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 16 hours. Upon cooling, the reaction mixture was diluted with CH2Cl2 and filtered with CH2Cl2/MeOH washing. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 0%-15% EtOAc/CH2Cl2 at 30 mL/min. Concentration of appropriate fractions provided the title compound (32 mg, 30% yield). LC/MS: Example 109A @ 2.49 min (RT) (Condition G). MS (ES): m/z=262.42 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 9.38 (1 hr, s), 8.71 (1 hr, s), 8.08-8.15 (1 hr, m), 7.96 (1 hr, dd, J=8.06, 1.01 Hz), 7.51-7.71 (4 hr, m), 7.39-7.51 (3 hr, m).