Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[C:25]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]([CH3:23])([CH3:24])[CH2:21][CH3:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(C)(C)c1ccc(Oc2ccncc2N)c(C(C)(C)CC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(Oc2ccncc2NC(=O)c2ccccc2)c(C(C)(C)CC)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Amino-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine (3.0 g, 9.2 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 10° C. Benzoyl chloride (1.3 g, 9.2 mmol) in tetrahydrofuran (10 mL) was added dropwise. Triethylamine (0.93 g, 9.2 mmol) in tetrahydrofuran (5 mL) was added and the mixture warmed to room temperature and stirred for 2 hours. The mixture was submitted to standard aqueous acidic workup. The crude solid obtained was recrystallized from acetonitrile to yield the title product as a white solid in 80% yield, m.p. 253° C. Mass spectral and NMR data were consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=2[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CS(O)(=O)=O>O1CCOCC1>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:7]3[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=3[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cnc(Cl)c2ccn(CC)c12
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(CC)c12

Procedure:
A mixture of ethyl 4-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.095 g), 3-chloroaniline (0.079 ml) and methanesulfonic acid (0.049 ml) in 1,4-dioxan (2.5 ml) was irradiated at 180° C. for 30 minutes with microwaves. The residue was partitioned between ethyl acetate and water, the aqueous was separated, basified with an aqueous 2M sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown oil (0.160 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:35][C@H:31]1[CH2:32][CH2:33][CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.0 mg, 0.0592 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.1 mg, 0.0571 mmol) and HATU (73.6 mg, 0.194 mmol), DMF (1.50 mL) was added, followed by DIPEA (84.8 mg, 0.656 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.9 mg, 22%). LCMS calc. for C24H23F3N5O2 (M+H)+: m/z=470.2. found 470.2.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=[O:9])=CC=1.[NH2:13][C:14]1[N:18]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:17]=[C:16]([C:31]#[N:32])[C:15]=1[C:33]#[C:34][CH3:35].C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:13][C:14]1[N:18]([C:19]2[C:20]([Cl:30])=[CH:21][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:23][C:24]=2[Cl:25])[N:17]=[C:16]([C:31]#[N:32])[C:15]=1[C:33](=[O:9])[CH2:34][CH3:35]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Toluenesulphonic acid monohydrate (2.92 g) was added to a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(prop-1-yn-l-yl)pyrazole (WO-A-97107102; 2.1g) in acetonitrle (40 ml) and the mixture stirred at room temperature for 1 hour. Further p-toluenesulphonic acid monohydrate (1.0) was added and this mixture stirred at room temperature for 16 hours. Further acetonitrile (20 ml) and yet more p-toluenesulphonic acid monohydrate (1.0 g) were added and stirring continued for 1 hour, then the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (500 ml) and extracted with ether (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and evaporated under reduced pressure, then the residue purified by column chromatography on silica gel (70 g), using dichloromethane as eluant, to yield the title compound as a pale brown solid, m.p. 167-169° C. δ(CDCl3): 1.26 (t,3H), 3.03 (q,2H), 5.83 (br.s,2H), 7.80 (s,2H). MS (thermospray): M/Z [M+H] 377.2; C14H9Cl2F3N4O+H requires 377.0.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(Cl)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(Cl)ccc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(Cl)cc3n21
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (200 mg) was dissolved in 1,4-dioxane (3 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added to give a light red solution. Refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butyramide (165 mg) as light yellowish solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1)=O.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O>[OH:14][C:13]1[C:4]([C:2](=[S:35])[CH3:1])=[CH:5][C:6]2[C:7]([CH3:18])([CH3:17])[CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]=2[CH:12]=1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=S)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To 5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthyl methyl ketone (13.3 mg, 53.9 μmol) were added anhydrous toluene (1 mL) and Lawesson's reagent (32.0 mg, 80.9 mmol) followed by stirring at 120° C. for 24 hours. The reaction solution was poured into cold water and extracted by dichloromethane, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (12/1) as an elution solvent. The yield was 4.2 mg (30%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: c1ccncc1
Product: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=S)[nH]1
Yield: 73 %

Procedure:
A suspension of 2-amino-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidin-4(3H)one (2.56 g, 10 mmol) and phosphorus pentasulfide (2.5 g, 11 mmol) in pyridine (200 ml) was refluxed for 4 hours. The reaction mixture was cooled down and the precipitate was filtered off, yielding the pure title compound, which was used without any further purification (2 g, yield: 73%) and was characterised by its mass spectrum as follows: MS (m/z): 273 ([M+H]+, 100)
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH:66]=[CH2:67])[C:55]([O:57]CC)=[O:56]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:72])[C:68]([F:69])([F:70])[F:71])[C:55]([OH:57])=[O:56])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate prepared in Example 7, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH:10]([CH3:25])[CH2:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH3:25][CH:10]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:26]
Reactant: CC(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(CC1CCNCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-[3-(benzyloxy)-2-methyl-3-oxopropyl]piperidine-1-carboxylate was dissolved in 5 mL of anhydrous 4N HCl in dioxane and stirred at rt for 1 h. The reaction mixture was concentrated to afford benzyl 2-methyl-3-piperidin-4-ylpropanoate. ESI-MS calc. for C16H23NO2: 261; Found: 262 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)=[O:20])[C:14]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[N:65]1([C:28]([CH:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:19]([C:15]3[C:14]([CH3:31])=[C:13](/[CH:12]=[C:5]4\[C:6](=[O:11])[NH:7][C:8]5[C:4]\4=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)[NH:17][C:16]=3[CH3:18])=[O:20])[CH2:27][CH2:26]2)=[O:30])[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To the solution of 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid in 20 mL of DMF were added HATU (0.161 g, 0.424 mmol), DIEA (0.072 mL, 0.424 mmol) and morpholine (0.0737 g, 0.847 mmol). The reaction mixture was stirred at r.t. overnight. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethyl amine/methanol (5 mL). The precipitate was collected by filtration, washed with methanol and dried in vacuum to give title compound (69 mg, 32.9% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 2H), 7.53-7.55 (d, 1H), 6.81-6.92 (m, 2H), 3.95-3.96 (m, 1H), 3.29-3.54 (m, 8H), 2.64-2.67 (m, 1H), 2.39-2.41 (ds, 6H), 1.47-1.88 (m, 8H). LC/MS: 495.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]2[CH2:11][C:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:7]2)[C:5]1=[O:21])[CH:2]=[CH2:3].[Sn]>O.Cl>[CH2:1]([N:4]1[C:9](=[O:10])[CH:8]2[CH2:11][C:6]([C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)([CH2:7]2)[C:5]1=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: Cl
Agent: [Sn]
Solvent: O
Product: C=CCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.97 g of 3-allyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione and 5.2 g of tin powder in 14 ml of water and 14 ml of concentrated hydrochloric acid is stirred at 100° for 1.5 hours. After cooling to room temperature, the reaction mixture is diluted with a little water, filtered and rendered alkaline by the addition of sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate, and the organic phase is washed neutral with dilute sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Melting point 176°-178° (from ethyl acetate/petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:10]([CH:9]=1)[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])#[N:8]
Reactant: N#CCc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: N#CCc1ccc(O)c(C(=O)CCC(=O)O)c1

Procedure:
4-Hydroxybenzyl cyanide was reacted with succinic anhydride and aluminium chloride in a similar manner to that described in Example 11 (i) to give 3-(5-cyanomethyl-2-hydroxybenzoyl)-propionic acid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:30])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:31]([CH2:33][NH2:34])[OH:32]>CS(C)=O>[OH:32][CH2:31][CH2:33][NH:34][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:30])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1ccc(-c2cn(C)nn2)cc1OCc1csc2c(C(=O)NCCO)cnc(N)c12
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.11 mmol) (from Example 23 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The reaction mixture was purified by C18 column eluting with acetonitrile-water to give 4-amino-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 31.0 mg, 60%).
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[OH:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8]
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 75, Step D, 248 mg, 0.52 mmol) in a 5:2 mixture of methanol/tetrahydrofuran (7 mL) was added potassium carbonate (218 mg, 1.57 mmol). This mixture was stirred at room temperature overnight and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→3% methanol/chloroform) to give 150 mg (71%) of the title compound as a white solid. mp: 217-219° C. (dec); 1H NMR (CDCl3, 250 MHz) δ 9.66 (s, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.99 (m, 1H), 7.68-7.78 (c, 2H), 6.47 (d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.41 (s, 3H), 2.80 (t, 2H), 1.51 (d, 3H); MS (APCI) 404 (MH+); [α]D+13.4 (c 1.5, CHCl3).
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:5]=1.[Cl:22][C:23]([Cl:30])([Cl:29])[CH2:24][O:25][C:26](Cl)=[O:27]>>[Cl:22][C:23]([Cl:30])([Cl:29])[CH2:24][O:25][C:26]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][N:2]([CH3:1])[CH2:3][C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)[N:5]=2)[CH2:17][CH2:18]1)=[O:27]
Reactant: CN(Cc1nc(-c2ccncc2)no1)CC1CCNCC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Product: CN(Cc1nc(-c2ccncc2)no1)CC1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1

Procedure:
The tert-butoxycarbonyl group of 4-{[methyl(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}piperidine-1-carboxylic acid tert-butyl ester (Example 124) was removed using the procedure described in Example 51 to afford methylpiperidin-4-ylmethyl-(3 pyridin yl-[1,2,4]oxadiazol-5-ylmethyl)amine: RT=0.75 min; m/z (ES+)=288.0 [M+H]+. Derivatisation of methylpiperidin-4-ylmethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine with 2,2,2-trichloroethylchloroformate, using the procedure described for Example 52, afforded the title compound: RT=3.51 min; m/z (ES+)=461.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[C:24]2[N:23]=[C:22](Cl)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Br:15][C:16]1[C:24]2[N:23]=[C:22]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH2:10][CH2:11]3)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1

Procedure:
The piperazine from step (a) above (162 mg, 0.7 mmol) and 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (168 mg, 0.56 mmol, Example 6b) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 176-179° C. MS (ESI, pos. ion) m/z: 495 (M+1).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22](B(O)O)=[C:21]([CH3:29])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([Pb+3:17])=[C:21]([CH3:29])[CH:20]=1
Reactant: Cc1cc(Br)cc(C)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Br)cc(C)c1[Pb+3]
Temperature: 40 °C
Yield: 25.1 %

Procedure:
To a mixture of lead tetraacetate (112.16 g, 0.25 mol) and mercuric diacetate (4.8 g, 0.015 mol), thoroughly flushed with nitrogen, is added anhydrous chloroform (480 ml). This mixture is warmed to 40° C. and 4-bromo-2,6-dimethylphenylboronic acid (48 g, 0.21 mol) is added in one portion and the mixture is stirred and heated at this temperature for 4 hours. After cooling in an ice bath, powdered anhydrous potassium carbonate (350 g) is added rapidly followed by rapid stirring for 5 minutes. The solids are removed by filtration and the filtrate is concentrated to approximately a quarter of its volume. Hexane is added to induce crystallization and the solvents evaporated under reduced pressure. Trituration with hexane gives 4-bromo-2,6-dimethylphenyl lead triacetate (30 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]12[CH2:17][CH:16]1[C:15](=[O:18])[O:14][C:13]2=[O:19].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([C@H:16]2[CH2:17][C@H:12]2[C:13]([OH:19])=[O:14])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.6 %

Procedure:
To a cold (0° C.) stirred solution of bromobenzene (9.09 g, 57.89 mmol) and AlCl3 (18.36 g, 137.84 mmol) in dry DCM (150 mL) was added 3-oxabicyclo[3.1.0]hexane-2,4-dione (5.40 g, 48.24 mmol). The reaction mixture was stirred at rt for 3 days. The dark-red solution was then poured into ice-cold water (120 mL), and conc. HCl (10 mL) was added. The solution was stirred for few minutes, and the layers were separated. The aqueous layer was extracted with DCM and the combined organic phases were washed with water, brine, dried over Na2SO4 and concentrated to give cis-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.69 g, 65%). LC-MS ret. time 2.50; m/z 270 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.54 (m, 1H), 1.85 (m, 1H), 2.37 (m, 1H), 2.88 (m, 1H), 7.65 (m, 2H), 7.90 (m, 2H).