Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:41])([F:40])C([O-])=O.[Na+]>[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:36]([F:41])([F:40])[F:35])=[CH:11][C:10]=1[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1)N1Cc2ccccc2C1
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Product: O=C(c1cc(C(F)(F)F)c(OCc2ccccc2)cc1OCc1ccccc1)N1Cc2ccccc2C1
Temperature: 150 °C
Yield: 29.3 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-bromo-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanone (491 mg, 0.95 mmol), sodium trifluoroacetate (649 mg, 4.8 mmol) and copper (I) iodide (364 mg, 1.91 mmol) were dried under vacuum (0.04 mbar) for 6 hours. The flask was flushed with nitrogen, DMF (5 mL) was added and the mixture heated at 150° C. for 17 hours. After cooling to r.t., the mixture was diluted with DCM (100 mL) and filtered through Celite, rinsing with DCM. The filtrate was concentrated to dryness and the residue was partially purified by flash chromatography on silica (ethyl acetate/petrol gradient, 0-20%). The purest fraction was recrystallised from methanol to afford the title compound as a white solid (140 mg, 29%). 1H NMR (methanol-d4) 7.60 (1H, s), 7.48-7.44 (2H, m), 7.40 (2H, t), 7.37-7.21 (m, 9H), 7.17 (1H, d), 7.02 (1H, s), 5.29 (2H, s), 5.24 (2H, s), 4.88 (2H, s), 4.62 (2H, s). MS: [M+H]+ 504.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1(=[O:16])=[O:15].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.CCOCC>[CH2:17]([NH:21][C:22]([NH:14][S:11]([C:10]1[C:4]2[S:3](=[O:16])(=[O:15])[N:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:12])=[O:13])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1S(=O)(=O)N(C)C2
Reaction time: 16 h

Procedure:
A suspension of 13.0 g of 2-methyl-2,3-dihydro-1,2-benzisothiazole-7-sulfonamide-1,1-dioxide, 11.2 ml of butyl isocyanate and 13.8 g of potassium carbonate in 200 ml of dry methyl ethyl ketone was heated at reflux for 2 hours. 13.8 g of potassium carbonate was added and heating was continued for an additional 16 hours. The mixture was cooled, the solvent was decanted from the solids, concentrated in vacuo, the residue dissolved in ethyl acetate and washed with saturated aq. NaHCO3. The aqueous wash was added to the originalsolids diluted with water and acidified to pH ~3 with dilute HCl. Themixture was extracted with methylene chloride, the extract was washed with water and brine, dried and concentrated in vacuo leaving a solid which wasslurried in ether and filtered to give 13.24 g of the title compound as a white powder, m.p. 162°-164° C.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN([CH:27]([CH3:29])[CH3:28])C(C)C.Cl>ClCCl>[CH2:19]([O:18][C:16]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)=[O:17])[C:28]1[CH:27]=[CH:29][CH:6]=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 1 (29.5 mg, 0.10 mmol) and DIEA (51 μl, 0.30 mmol) in dichloromethane (1 ml) is added benzyl chlorofornate (16 μl, 0.11 mmol). The reaction mixture is stirred at rt for 1 h, 1 N aqueous HCl (2 ml). The aqueous layer is extracted twice with dichloromethane. The combined organic layers are washed with water, saturated NaHCO3 solution, then are concentrated to dryness to afford crude ethyl (2-benzyloxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate: tR (LC-1) 2.52 min; ESI-MS (positive ion): m/z 393.19 [M]+ (calcd 392.45 for C23H24N2O4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:36])([F:38])[F:37]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 4-fluoro-3-(trifluoromethyl)benzaldehyde in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as an off-white solid. MS (m/e)=548.1 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([N:17]1[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=[C:18]1[C:28]([O:30]CC)=O)[C:11]2=O)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[O:30]=[C:28]1[NH:37][C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]=3[CH2:9][C:10]=2[N:17]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=[C:18]12
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1cn(C2Cc3c(CC(=O)OCC)cccc3C2=O)c(C(=O)OCC)n1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)OCC)c1C3
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A mixture of 1.63 g of ethyl 1-[4-(ethoxycarbonylmethyl)-1-oxoindan-2-yl]-4-(ethoxycarbonylmethyl)imidazole-2-carboxylate, 15 ml of acetic acid and 2.83 g of ammonium acetate is heated at reflux for 5 hours. The heating is stopped, 1.4 g of ammonium acetate are added and the refluxing is continued for 2 hours. The reaction mixture is poured over 100 ml of crushed ice and extracted with 3×50 ml of dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated in a rotary evaporator. The evaporation residue is suspended in 15 ml of ethyl acetate to give 0.8 g of diethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2,9-diacetate in the form of a beige solid [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm, (250 MHz): 1.25 (6H, m, 2 CH3), 3.80 (4H, s, 2 CH2CO2Et), 4.00 (2H, s, CH2), 4.15 (4H, q, J=6 Hz 2 OCH2), 7.15 (1H, d, J=8 Hz, arom. CH), 7.40 (1H, t, J=8 Hz, arom. CH), 7.80 (1H, d, J=8 Hz, arom. CH), 7.90 (1H, s, arom. CH), 12.4 (1H, s, CONH)].
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23].N1C=CC=CC=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:13])=[O:12])=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)c(Cl)c1
Yield: 49.3 %

Procedure:
A solution of 70 (2.5 g; 9.36 mmol) and methyl 3-aminothiophene-2-carboxylate (1.62 g; 10.30 mmol) in anhydrous pyridine (12.0 mL; 144 mmol) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 20% v/v) to give the title compound as a clear oil (1.79 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([CH2:29][NH2:30])[CH:27]=[CH:28][C:21]1=2>>[O:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([CH2:29][NH:30][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]5[O:15][CH2:16][CH2:17][O:18][C:11]=5[CH:10]=4)[C:5]([F:19])=[CH:4][N:3]=3)[CH:27]=[CH:28][C:21]1=2
Reactant: NCc1ccc2c(c1)CCO2
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(NCc2ccc3c(c2)CCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted to give N2-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 21.43 min.; purity: 97.5%; MS (m/e): 395.05 (MH+).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:21]1[C:15]2[S:14][C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])=[CH:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NO
Reactant: N#Cc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 80 °C

Procedure:
120 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzo-thiophene-2-carboxamide hydrochloride, 45.0 mg (0.65 mmol) of hydroxylamine hydrochloride and 119.2 mg (0.86 mmol) of potassium carbonate in 1.5 ml of an 8:1 mixture of water and ethanol are heated at 80° C. for 18 h. The mixture is purified by preparative HPLC. The product fractions are combined and concentrated, acetonitrile and 1N aqueous hydrochloric acid (3:1) are added and the mixture is then again concentrated and dried under high vacuum. 58 mg (30.3% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19])[CH:14]=[CH:15][CH:16]=1)#[N:10]>ClCCl>[O:8]=[C:2]1[C:3](=[O:5])[N:17]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:9]#[N:10])[C:18](=[S:19])[N:20]1[CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(NC(=S)Nc1cccc(C#N)c1)C(C)(C)C
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2cccc(C#N)c2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Ethyl chlorooxoacetate (1.03 mL, 9.17 mmol) was added to a stirring solution of the above thiourea (1.19 g, 4.59 mmol) in dichloromethane (30 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and filtration afforded 1.167 g (81%) of 3-[4,5-dioxo-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidin-1-yl]-benzonitrile as a yellow solid: mp 168.1–168.7° C.; 1H NMR (DMSO-d6): δ8.00 (d, 1H), 7.84 (s, 1H), 7.75 (m, 2H), 4.83 (q, 1H), 1.47 (d, 3H), 1.01 (s, 9H); IR (KBr): 3500, 2970, 2230, 1765, 1600 cm−1; MS (m/z) 315 (M+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:19]([O:18][C:16]([CH:15]1[CH2:21][CH2:22][N:12]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:13][CH2:14]1)=[O:17])[CH3:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
A solution of benzyl chloroformate (95 g, 0.56 mol) in dichloromethane (200 ml) was added dropwise to an ice-bath-cooled, stirred mixture of ethyl isonipecotate (87 g, 0.55 mol), sodium carbonate (60 g, 0.57 mol) and dichloromethane (200 ml) over 70 minutes. The mixture was stirred at ambient temperature for 2.5 days and filtered though a pad of Celite™. The filtrate was concentrated in vacuo. The residue was partitioned between 2M aqueous hydrochloric acid and diethyl ether. Organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel (ethyl acetate/iso-hexane) to give the title product (152 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:3]=1[N+:16]([O-])=O>C(O)C.C(O)(=O)C.[Zn]>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[C:3]([NH2:16])=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Nc1ccnc(Cl)c1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c(Cl)ncnc1Nc1ccnc(Cl)c1
Reaction time: 1 h
Yield: 128.4 %

Procedure:
N-(6-Chloro-5-nitro-4-pyrimidinyl)-N-(2-chloro-4-pyridyl)amine (2.2 g, 7.6 mmol) was suspended in 44 ml ethanol and 4.4 ml acetic acid, and 2.2 g zinc powder was added little by little thereto at 0° C. The reaction solution was returned to room temperature and stirred for 1 hour, and then the insoluble matters were filtered off. The filtrate was concentrated and suspended in water, and the resulting solid was collected by filtration and air-dried, to give 2.5 g of the title compound in crude form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].C(OC([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](O)=O)[CH2:19][CH2:18]1)=O)(C)(C)C.OP(O)(O)=O.S1(CCCC1)(=O)=O>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:24]([CH2:23][CH:20]3[CH2:21][CH2:22][NH:17][CH2:18][CH2:19]3)[S:9][C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccc(Br)cc1S
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: Brc1ccc2nc(CC3CCNCC3)sc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
2-Amino-5-bromobenzenethiol (326 mg, 1.597 mmol), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (480 mg, 1.973 mmol), PPA (115% as H3PO4) (1637 mg, 6.82 mmol), and sulfolane (3.9 mL) were placed in a microwave vial and heated carefully with vial open to air at 80° C. for 10 min. The vial was then sealed and heated in microwave at 140° C. for 20 min. The mixture was diluted with MeOH, and purified via preparative HPLC (PHENOMENEX® Axia 5u C18 30×100 mm, Flow rate: 40 mL, Solvent A: 90% H2O and 10% MeOH with 0.1% TFA, Solvent B: 90% MeOH and 10% H2O with 0.1% TFA. 20% to 100% B in 10 min gradient, stop at 12 min, the product RT=6.86 min) to afford Compound 41A as an orange solid (380 mg, 76% yield). 1H NMR (400 MHz, methanol-d3) δ 8.16 (d, J=1.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.63 (dd, J=8.7, 1.8 Hz, 1H), 3.40 (d, J=12.8 Hz, 2H), 3.14 (d, J=7.1 Hz, 2H), 3.01 (t, J=12.2 Hz, 2H), 2.27 (tdt, J=11.2, 7.3, 3.5 Hz, 1H), 2.02 (d, J=12.6 Hz, 2H), 1.56 (td, J=14.9, 3.7 Hz, 2H). LCMS (m/z)=311 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:23](=O)[CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.O=P(Cl)(Cl)Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][C:9]2[C:10]([N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:22]=[C:23]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: O=C(CC(F)(F)F)Nc1ccccc1Nc1ncccc1CC(c1cccnc1)c1cccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)(F)Cc1nc2ccccc2n1-c1ncccc1CC(c1cccnc1)c1cccnc1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
To a solution of N-(2-{[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]amino}phenyl)-3,3,3-trifluoropropanamide (127 mg) in 6 mL of dioxane was added 500 uL of POCl3. Immediate precipitation was observed. The reaction was heated at 100 C for 24 h, giving a sluggish reaction. The reaction was cooled to 0 C and carefully quenched with saturated aqueous sodium bicarbonate. then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and concentrated. The resulting crude mixture of starting material and desired product was dissolved in 4 mL of dioxane. This solution was added dropwise to 10 mL of POCl3 stirring at 50 C. The mixture was heated at 100 C for 8 h, then cooled to room temperature and concentrated in vacuo. CH2Cl2 was added to the residue, and the resulting solution was cooled to 0 C and neutralized slowly with saturated aqueous sodium bicarbonate, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and purified by flash chromatography. A second purification by reverse phase HPLC provided 127 mg of 1-[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]-2-(2,2,2-trifluoroethyl)-1H-benzimidazole as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (dd, J=4.6, 1.7 Hz, 1H), 8.43 (d, J=4.4 Hz, 2H), 8.31 (d, J=1.7 Hz, 1H), 8.24 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.69 (dd, J=7.8, 1.5 Hz, 1H), 7.40-7.35 (m, 2H), 7.31-7.28 (m, 1H), 7.22-7.20 (m, 1H), 7.18-7.11 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 4.08 (t, J=7.8 Hz, 1H), 3.73-3.64 (m, 1H), 3.52-3.43 (m, 1H), 3.29-3.21 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18][OH:19].Cl.N1C=CC=CC=1>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:18][OH:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(C=NO)c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (3-formyl-phenoxy)-acetic acid tert-butyl ester (2.05 g, 8.68 mmol) in MeOH (30 mL) was added NH2OH.HCl (0.66 g, 9.54 mmol) and pyridine (3.5 mL, 43.4 mmol) and the reaction was stirred for 2 hours. The MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (1.99 g). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.23-7.28 (m, 2H), 7.12 (m, 1H), 6.93 (d, 1H), 4.51 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [Br:1]Br.[C:3]12[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8][C:7](=[O:14])[O:6][C:4]2=[O:5]>O>[Br:1][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:14])[O:6][C:4](=[O:5])[C:3]=2[CH:13]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: BrBr
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Bromine (35 mL, 660 mmol) was added dropwise to a suspension of isatoic anhydride (100 g, 610 mmol) in 1.6 L water at 50° C. This temperature was maintained for an additional 2 hours. After cooling the solution to room temperature, the solid was filtered and washed twice with water and twice with acetone, yielding 125.6 g (85%) 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione as a pink solid.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1C#N>ClCCl>[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#Cc1cnccn1
Solvent: ClCCl
Product: c1ccc2c(c1)nc1snc(-c3cnccn3)n12
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.1 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-α]benzimidazole-3(2H)-one (300 mg, 1.213 mmol) and pyrazinecarbonitrile (319 mg, 3.03 mmol) in 8 mL of dicloromethane was stirred at room temperature for 36 hr. The precipitate was filtered and washed with dichloromethane to give 0.28 g (91%) of 3-(2-pyrazinyl)-1,2,4-thiadiazolo[4,5-α]benzimidazole as a white solid; 1H NMR (CDCl3) δ 7.32 (t, 1H, ArH), 7.50 (t, 1H, ArH), 7.83 (d, 1H, ArH), 8.67 (d, 1H, ArH), 8.87 (br.d, 2H, py-H), 9.59 (s, 1H, py-H); mp 255-256.5° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[N:26]=[C:25](I)[C:24]([NH2:28])=[CH:23][CH:22]=1.[CH2:29]([O:31][C:32](=[O:39])[C:33]([CH3:38])([CH3:37])[CH2:34][C:35]#[CH:36])[CH3:30]>CCN(CC)CC.Cl[Pd]Cl.[Cu]I>[CH2:29]([O:31][C:32](=[O:39])[C:33]([CH3:38])([CH3:37])[CH2:34][C:35]#[C:36][C:25]1[C:24]([NH2:28])=[CH:23][CH:22]=[C:21]([Cl:20])[N:26]=1)[CH3:30]
Reactant: C#CCC(C)(C)C(=O)OCC
Reactant: Nc1ccc(Cl)nc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CC#Cc1nc(Cl)ccc1N

Procedure:
PdCl2 (0.200 g, 1.13 mmol), CuI (0.214 g, 1.13 mmol), and PPh3 (0.590, 2.25 mmol) were suspended in NEt3 (150 mL) and stirred under N2. 6-Chloro-2-iodo-pyridin-3-ylamine (5.7 g, 2.24 mmol) was added, followed by 2,2-dimethyl-pent-4-ynoic acid ethyl ester (5.2 g, 3.37 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([C:21]1[N:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH:5][C:3]([O:2][CH3:1])=[O:4])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1C(C)=O

Procedure:
A suspension of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine (500 mg.) in 10 ml. of acetic anhydride is treated as in Example 7 to yield 3-acetyl-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)([OH:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[F:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](S(Cl)(=O)=O)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:35]=[CH:34][C:27]([C:28]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:12]3([OH:15])[CH2:11][CH2:10][N:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[CH2:18][CH2:19]2)=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1nccc(N2CCC(O)(CN3CCNCC3)CC2)n1
Reactant: O=C(c1ccc(F)cc1)S(=O)(=O)Cl
Agent: Cl
Product: Cc1nccc(N2CCC(O)(CN3CCN(C(=O)c4ccc(F)cc4)CC3)CC2)n1

Procedure:
Using an analogous procedure to that described in Example 14, 1-(2-methylpyrimidin-4-yl)-4-(1-piperazinomethyl)piperidin-4-ol hydrochloride was reacted with 4-fluorobenzoylsulphonyl chloride to give 1-(4-fluorobenzoyl)-4-[1-(2-methylpyrimidin-4-yl]-4-hydroxy-4-piperidylmethyl]piperazine m.p. 114-117° C.