Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C[Al](C)C.[O:22]1[CH2:24][CH:23]1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>ClCCl>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([O:26][CH2:25][CH:23]([OH:22])[CH2:24][N:3]2[CH2:4][CH:5]3[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CNC2
Reactant: N#Cc1ccc(OCC2CO2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(CC(O)COc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl 3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation D; 1.68 g, 7.0 mmol) in dichloromethane (35 mL) at 25° C. under nitrogen was added trimethylaluminum (3.75 mL of 2.0 M in hexanes, 7.0 mmol). After stirring at 25° C. for 30 min, 4-(2-oxiranyl-methoxy)benzonitrile (Preparation E(i); 1.22 g, 7.0 mmol) was added in one portion, and the mixture was stirred overnight. The mixture was quenched with 3 N NaOH (11.5 mL) and stirred for 1 h. Water (30 mL) was added, and the aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford an oil. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 2.35 g (81%) of the subtitle compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of 278 mg (0.76 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 5 ml of N,N-dimethylformamide was treated with 0.39 ml (2.3 mmol) of dibutylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated, the residue was dissolved in 20 ml of methylene chloride and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and evaporated. The crude product was chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1). There were obtained 250 mg of 8-chloro-3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted with ethereal hydrochloric acid into the hydrochloride. By crystallization from acetonitrile there were obtained 151 mg (39%) of 8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.3) of m.p. 165°-175° (dec.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CCN(c1ncccc1CC(C)C)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-[N-ethyl-N-(3-(2-methyl-1-propenyl)-2-pyridinyl)amino]piperidine (XXII, EXAMPLE 17, 0.67 g, 1.92 mmol), Pearlman's catalyst (0.1 g), CDI (0.31 g, 1.92 mmol) and pyrrole-2-carboxylic acid (0.213 g, 1.92 mmol), the title compound is obtained, HRMS Calcd. for C21H30N4O=354.2419, found=354.2413.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[I:34]C1C=CC(OC2C=CC(S(Cl)(=O)=O)=CC=2)=CC=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([I:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(I)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(I)cc2)cc1

Procedure:
Compound 4e was prepared following the procedure described for 4a with reagent quantities adapted to the amount of starting material 3e (0.71 g, 1.81 mmol). Yield: 1.04 g, 1.64 mmol, 99% (white solid). 1H-NMR (DMSO-d6): δ 7.96 (d, 3J=8.5 Hz, 2H, ArH), 7.59 (d, 3J=8.5 Hz, 2H, ArH), 4.07 (s, 4H, 2×CH2CO2H), 1.40 (s, 18H, 2×CO2tBu).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:21])[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[C:2]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:21])[CH2:15]1)([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=O)C(C)C1
Reaction time: 6 h

Procedure:
Ethyl chloroformate (3.0 g, 26.7 mmol) was added to a stirred solution of 1-benzyl-3-methyl-4-piperidinone (2.0 g, 9.85 mmol) in benzene (30 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 6 hr and concentrated to dryness to give 1-carbethoxy-3-methyl-4-piperidone as oil. Yield 1.4 g (77%), C9H15NO3, m/z 186 (M+1).
Reaction SMILES: O[C:2]1([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:47]2)=CC=1>C1(C)C=CC=CC=1>[SH:47][C:2]1([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)CCCC2(S)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 5-hydroxy-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (Example 1d1) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH2:17][CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH2:17][CH3:18])[C:19]([F:21])([F:22])[F:20]
Reactant: CCc1[nH]n(-c2ccccc2)c(=O)c1C(O)(C(=O)OC)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCC1=NN(c2ccccc2)C(=O)C1=C(C(=O)OC)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 3-ethyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (172 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (163 mg).
Reaction SMILES: C(O)(=O)C.FC(F)(F)OC1C=CC([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=CC=1.CN1C(C)=C(S(Cl)(=O)=O)C(C)=N1>N1C=CC=CC=1>[C:15]1(=[O:24])[C:16]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:18][NH:14]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Agent: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C1NCCC12CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 1167.2 %

Procedure:
2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (0.02 g, 0.05 mmol) was dissolved in pyridine (0.5 ml) at room temperature and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (0.013 g, 0.06 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in AcOEt and washed with 0.1M HCl and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography (4:1 AcOEt/heptane) to yield 2-(4-trifluoromethoxy-phenyl)-8-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,8-diaza-spiro[4.5]decan-1-onel)-2,8-diaza-spiro[4.5]decan-1-one as an off-white solid (0.09 g, 31%). MS (ESI): 487.3 (MH+)
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Product: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine Mp. 222° C.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].C(=O)([O-])O.[Na+].[Cl-].[Na+]>O>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:10][CH:9]=1)[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(S(=O)(=O)O)cc1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
33 ml (0.6 mol) of conc. sulfuric acid was added to 62 ml (0.5 mol) of ethylbenzene, and the mixture was stirred for 1.5 hours under heating at 120 to 130° C. Layer separation will occur if unreacted ethylbenzene still remains, so the reaction was terminated when no layer separation was confirmed, and a solution containing p-ethylbenzenesulfonic acid as the major component was thus obtained. This solution was poured into 150 ml water and neutralized partially with sodium hydrogen carbonate, and the sodium chloride was added to precipitate crystals ol sodium p-ethylbenzene sulfonate. The resulting crystals were separated by filtration and dried in vacuo. This sodium p-ethylbenzenesulfonate is easily soluble in water and sparingly soluble in ethanol. A 1H-NMR spectrum of the resulting crystals is shown in FIG. 1.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: COC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 77 %

Procedure:
An 18-mL test tube was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (30 mg, 0.1 mmol, 1 eq. Synthesis of this compound was described in step 1 of EXAMPLE 1) and methyl 2-(4-aminophenyl)acetate (33 mg, 0.2 mmol, 2 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane followed by 1˜3% of MeOH in dichloromethane as eluent to give methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate (31 mg, 77% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:21]=2[N:20]=1.[Cl:40][C:41]1[N:46]=[C:45](Cl)[CH:44]=[CH:43][N:42]=1.[F-].[K+]>C1COCC1.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]>[Cl:40][C:41]1[N:46]=[C:45]([C:5]2[CH:4]=[C:3]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]4[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:21]=4[N:20]=3)[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[N:6]=2)[CH:44]=[CH:43][N:42]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccc(C(F)(F)F)cc3n2COCC[Si](C)(C)C)c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccc(C(F)(F)F)cc3n2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Oxo-5-[6-tri-fluoromethyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-1-(2-trimethylsilanylethoxymethyl)-1,6-dihydropyridazine-3-boronic acid, 2,4-di-chloropyrimidine, potassium fluoride and tris(dibenzylideneacetone)dipalladium(0) are dissolved in dry THF and degassed with argon for 10 minutes. Tri-tert-butyl-phosphonium tetrafluoroborate is added, and the reaction mixture is stirred at room temperature for 16 hours. LC-MS analysis shows complete conversion. The solvent is removed in a rotary evaporator, the residue is dissolved in DMF and the crude product is purified by preparative RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)). MS (ES+) m/z 653 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:8]=[N:7]1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:8]=[N:7]1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)Cn1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)cn1
Product: CCOC(=O)Cn1cc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: [4-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyrazol-1-yl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13]>C(OCC)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][NH:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1cccc(N)c1
Solvent: CCOCC
Product: N#Cc1cccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from 3-amino-benzonitrile (Fluka) and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 138-142° C. (diethylether)
Reaction SMILES: [NH2:1][C:2](=[O:33])[CH:3]([OH:32])[CH:4]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][N:24]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CS(C)=O>[NH2:1][C:2](=[O:33])[C:3](=[O:32])[CH:4]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][N:24]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1ncc(-c2ccccc2)[nH]1
Solvent: CS(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1ncc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)nicotinamide (60 mg, 0.136 mmol) in a mixture of 2 ml of DMSO and 10 ml of dichloromethane IBX-polystyrene was added (371 mg, 0.408 mmol), and the reaction mixture stirred for 16 hours at room temperature. The polymer was filtered off, washed with dichloromethane, the combined organic layers washed with water, dried and evaporated to dryness. The remaining oily residue was treated with water to give a yellow solid which was filtered off and dried again. To a solution of the obtained solid in 20 ml of ethylacetate (EtOAc) two drops of 4N HCl in dioxane were added, and the resulting precipitate filtered off. Recrystallisation of the crude product from 15 ml of ethylacetate yielded 31 mg of the title compound as solid.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[Br:17][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(-c2ccccc2)c1
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: CC(Br)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Yield: 0 %

Procedure:
To a solution of 3.97 g (20 mmol) of 3-(1-hydroxyethyl)biphenyl in 60 ml of dry diethyl ether was added dropwise 2.70 g (9.0 mmol) of phosphorous tribromide with ice-cooling, and the mixture was further stirred with ice-cooling for 3 hours. To the reaction solution were added ice water and tert-butyl methyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, dried and concentrated to obtain 3.73 g (14.28 nmol) of 3-(1-bromoethyl)biphenyl as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:15][CH3:16])[C:4]=1[CH:17]=O.COC1C2C(=CC=CC=2)C(OC)=CC=1/[CH:33]=[C:34](\C)/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:15][CH3:16])[C:4]=1/[CH:17]=[C:34](\[CH3:33])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: COc1c(C=O)c(SC)c(OC)c2ccccc12
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(C)=C/c1c(SC)c(OC)c2ccccc2c1OC

Procedure:
Compound 98h was prepared from 57 (0.308 g, 1.17 mmol) as described above for 28a to give 0.231 g (0.667 mmol, 55%) of the product as an amorphous yellow solid following flash chromatography (1:9 EtOAc:hexanes) and recrystallization from Et2O/hexanes. (0.165 g E; 0.065 g E/Z)
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:22][C:21]2=[O:29])[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[CH:17]1([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:21]2=[O:29])[CH2:19][CH2:18]1
Reactant: OCc1nc2ncccc2n1CCCCF
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCCF)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a suspension of (1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 42-5 (958 mg, 4.3 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (950 mg, 5.15 mmol) and triphenylphosphine (1350 mg, 5.15 mmol) in 30 ml dry THF was added (E)-diïsopropyl diazene-1,2-dicarboxylate (1.26 ml, 6.43 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (1036 mg, 63%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCCl)c2n1
Reactant: C1CCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(6-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-amino-pyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 240. NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.60-4.65 (2H, br. s), 6.57 (1H, d, J=8.6), 7.40 (1H, s), 8.45 (1H, dd, J=8.6, 2.2), 9.17 (1H, d, J=2.2). MS (ESI+): MH+490.18 (100%)