Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1NC=CN=1.C1(S([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](B(O)O)=N2)(=O)=O)C=CC=CC=1.P([O-])([O-])(O)=O.[Na+].[Na+]>O1CCOCC1.O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:2]1
Reactant: Brc1ncc[nH]1
Reactant: O=S(=O)(c1ccccc1)n1nc(B(O)O)c2ccccc21
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: 110 °C

Procedure:
A mixture of bromoimidazole Int-22a (98 mg, 0.20 mmol), 1-(phenylsulfonyl)-3-indazole boronic acid (73 mg, 0.24 mmol) and sodium hydrogen phosphate (86 mg, 0.61 mmol) in 1,4-dioxane (4 mL) and water (2 mL) at r.t. was purged with nitrogen gas for 5 min in a microwave vial. Tetrakistriphenylphosphorous palladium was added. The mixture was heated in a microwave reactor at 110° C. for 1 h. Water and ethyl acetate were added, and the layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (MgSO4) and filtered. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave indole Int-22b (112 mg, 84%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.N1C=CC=CC=1.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7]1
Reactant: CCCCC(=O)Cl
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of Intermediate 9 (0.028 g) in dichloromethane (2 ml) containing a suspension of polyvinyl pyridine (0.1 g) was treated with valeryl chloride (0.018 ml), and the mixture was shaken at 20° C. for 16 h. Tris (2-aminoethyl)amine polystyrene scavenger resin (Argonaut Technologies, 4.46 mmol/g; 0.067 g) was added, and the mixture was shaken at 20° C. for 2 h. The mixture was filtered and the filtrate applied directly to a silica gel cartridge (1 g Varian Bond Elut). Elution with chloroform, ether, and ethyl acetate gave the title compound (0.0225 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC=CC=4)=[C:25]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:24]=3)[OH:22])[CH2:14][C:13]=2[CH:42]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:43])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][CH2:20][C@H:21]([OH:22])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:24]=3)[CH2:14][C:13]=2[CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c(NS(C)(=O)=O)c1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1)CCC2
Yield: 89.1 %

Procedure:
A mixture of 2-[8-[(2R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxyethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid tert-butyl ester (353 mg) and 10% palladium on activated carbon (50% wet, 100 mg) in methanol (5 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours. After filtration, the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=10:1 to 5:1) to give 2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid tert-butyl ester (268 mg).
Reaction SMILES: [Br:1][C:2]1[C:27]([CH3:28])=[CH:26][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:8]2=[O:25])=[C:4]([F:29])[CH:3]=1.[ClH:30]>C(Cl)Cl.CO.O1CCOCC1>[ClH:30].[Br:1][C:2]1[C:27]([CH3:28])=[CH:26][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:8]2=[O:25])=[C:4]([F:29])[CH:3]=1
Reactant: Cc1cc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)cc1Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
(S)-tert-butyl 4-(3-(4-bromo-2-fluoro-5-methylphenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.3 g, 4.9 mmol) was dissolved in CH2Cl2:MeOH (9:1, 50 mL). 4N HCl in dioxane (10 mL) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to afford crude (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (2.0 g, 4.9 mmol, 101% yield) which was used without further purification.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)=[CH:9]2)(=O)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][N:33]=[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.823 g, 2.22 mmol) in DCM (5 mL) was added 2,4-dimethoxybenzylamine (0.38 mL, 2.53 mmol) and NEt3 (0.90 mL, 6.45 mmol). Mixture was cooled to 0° C. before TiCl4 solution (1M DCM, 1.45 mL, 1.45 mmol) was added dropwise via syringe pump over 30 min. Reaction was allowed to warm to room temperature and stirred overnight. Mixture was diluted with DCM (10 mL) and then quenched with NaHCO3 (aqueous saturated, 10 mL). Upon vigorous shaking organic phase was separated using a PTFE phase separator, dried over Na2SO4. Removal of the solvent afforded product (1.15 g, quant) as yellow oil, which was taken directly into next steps without purification.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)=[O:42])[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:49])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([OH:42])([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:49])[O:19][N:18]=1
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: CCOc1nc2c(C(=O)c3cnccn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCOCC
Product: Cc1noc(C)c1-c1cc(C(O)(c2cnccn2)c2c(F)cc(F)cc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To 1-bromo-2,4,6-trifluorobenzene (0.01 ml, 0.12 mmol) in diethyl ether (0.5 mL) at −78° C. was added n-butyllithium (0.13 mL, 0.14 mmol, 1.6 M in hexanes). After 30 tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylate (36.6 mg, 0.08 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 90 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (1.5 mL) was added hydrochloric acid (0.20 mL, 0.79 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (35-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrazin-2-yl)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[C:11]([CH2:19][CH:20](Br)[CH2:21][Br:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O.C(Cl)Cl>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH:20]([CH2:21][Br:22])[CH2:19][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)cc1CC(Br)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
(RS)-Acetic acid 4-benzyloxy-2-(2,3-dibromo-propyl)-phenyl ester (5.05 g, 11.3 mmol) was suspended in EtOH (50 ml) and sodium methoxide (620 mg, 11.3 mmol) added and the mixture stirred for 2 hr at ambient temperature. Distilled H2O (100 ml) and CH2Cl2 (100 ml) was then added and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (100 ml) and the combined organic extracts washed with satd. NaCl solution (100 ml). After drying with Na2SO4, filtration and evaporation a yellow oil resulted which was chomatographed over SiO2 (Merck 230-400 mesh) with CH2Cl2 to afford 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran as a yellow oil (3.0 g, 9.39 mmol, 83%), MS: m/e=318.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:11]([O:13]C)=O)=[O:8])=[CH:4][CH:3]=1.[OH-].[Li+].[CH3:23][N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])[C:11](=[O:13])[NH:35][C:32]1[CH:33]=[CH:34][C:27]2[CH2:26][CH2:25][N:24]([CH3:23])[CH2:30][CH2:29][C:28]=2[CH:31]=1
Reactant: CN1CCc2ccc(N)cc2CC1
Reactant: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)OC
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: [Li+]
Agent: [OH-]
Product: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2

Procedure:
The title compound is prepared from methyl 2-(5-chlorothiophen-2yl)carbonylamino-3-(2-methoxyethyloxy)propionate by lithium hydroxide saponification and subsequent reaction with 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with EEDQ analogously to Example 58(c).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C@@H]3C4(Cl)C(Cl)([Cl:22])C(Cl)(C(Cl)=C4Cl)[C@@H]3C(O)=O)=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1.NC1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.[C:63]1(=[O:77])[C:72]2[C:67]3[C:68](=[CH:73][CH:74]=[CH:75][C:66]=3C(=O)[O:64]1)[CH:69]=[CH:70][CH:71]=2>>[ClH:22].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C:66]3[CH:75]=[CH:74][CH:73]=[C:68]4[C:67]=3[C:72]([C:63]([OH:77])=[O:64])=[CH:71][CH:70]=[CH:69]4)=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: Nc1nc2ccc(NC(=O)[C@H]3[C@@H](C(=O)O)C4(Cl)C(Cl)=C(Cl)C3(Cl)C4(Cl)Cl)cc2[nH]1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Product: Nc1nc2ccc(NC(=O)c3cccc4cccc(C(=O)O)c34)cc2[nH]1
Yield: 96 %

Procedure:
Following the same procedure to synthesize (2S,3R)-3-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxylic acid hydrochloride (10), tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.082 g, 183 mmol) was reacted with benzo[de]isochromene-1,3-dione (0.036 g, 0.183 mmol) to give the title compound (0.067 g, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.43-11.21 (bs, 1H), δ 8.75 (s, 2H), δ 8.56 (q, 2H), δ 7.92 (t, 1H), δ 7.47 (s, 2H), δ 7.42 (d, 2H), δ 7.21 (d, 1H) ppm; 13C NMR (100 MHz, DMSO) δ 161.4, 151.9, 136.1, 133.2, 132.1, 130.9, 130.5, 129.4, 129.8, 129.3, 119.7, 119.3, 112.8, 106.9, 94.6 ppm; HRMS (ESI) Calcd for C19H14N4O3 (M+) 346.1066. Found 346.1061.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc2[nH]ccc2c1
Yield: 45.4 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.076 g) and 5-aminoindole (0.05 g) to give the title compound as a white solid (0.05 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[F:8][C:9]([F:15])([F:14])[C:10](OC)=[O:11]>CO>[F:8][C:9]([F:15])([F:14])[C:10]([NH:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:11]
Reactant: NC1CCNC1=O
Reactant: COC(=O)C(F)(F)F
Solvent: CO
Product: O=C1NCCC1NC(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A suspension of Intermediate 2 (181 g), methyl trifluoroacetate (218 ml) and methanol (2.6 l) was stirred for 2 h. The solvent was then removed in vacuo to afford the title compound as a cream solid (355 g). Mass spec. MNH4+ (found) 214 MNH4+ (calculated) 214
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].Br[C:26]1[S:30][C:29]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[S:30][C:29]([S:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)(=[O:32])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH:10]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)s2)CC1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 76%). MS (EI) 581.1 [(M)+]; mp 214° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[OH:8])[CH:2]=1.O1C[CH2:20][CH2:19][CH2:18]1.[H-].[Na+].C(Br)C=C>O>[CH2:20]([O:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[CH:19]=[CH2:18]
Reactant: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOC(c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.56 gm of the 3-pyridyl-2,4-dichlorophenylcarbinol and 60 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.37 gm sodium hydride added. The system was stirred for 75 additional minutes and 1.45 ml of allyl bromide was then added. The system was allowed to come to room temperature over 1/2-hour and stirred there for an additional 1 hour. Afterwards the system was heated at reflux for 18 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was then washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 1.73 gm of the 3-pyridyl-2,4-dichlorophenylcarbinol allylether and listed as compound number 3 in Table I.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:12])=[CH:5][CH:4]=1.[N:25]#[C:26][NH2:27].C(OCC)C>C(O)C>[ClH:1].[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:12])=[CH:7][CH:8]=1)[C:26]([NH2:27])=[NH:25]
Reactant: CCOC(=O)c1ccc(OC(=O)CCc2ccc(N)cc2)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1ccc(OC(=O)CCc2ccc(NC(=N)N)cc2)cc1

Procedure:
In 200 ml of ethanol were dissolved 28.6 g of the p-ethoxycarbonylphenyl β-(p-aminophenyl)-propionate hydrochloride obtained and 4.2 g of cyanamide, and the solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure to obtain an oily product, to which a mixture consisting of ethanol and diethyl ether was added and the solution was cooled, upon which crystals precipitated. The crystals were collected by filtration and recrystallized from an ethanol-diethyl ether mixture to obtain p-ethoxycarbonylphenyl β-(p-guanidinophenyl)propionate hydrochloride in the form of colorless crystals. Yield: 25.1 g (78%); melting point: 125°-127° C.; IR (cm-1): 3500-2550, 1750, 1708, 1670, 1599; MS: M+= m/e 355 (M.W. - HCl).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]2CC[C:17]=12.C1(C)C=CC=CC=1.O.[C:32](O)(=O)[CH3:33]>C(Cl)Cl>[CH:22]1[C:21]2[CH:18]=[CH:17][C:16]([N:15]3[C:11](=[O:12])[C:6]4=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]4[C:8]3=[O:10])=[CH:33][C:32]=2[CH:23]=1
Reactant: CC(=O)O
Reactant: Nc1cccc2c1CC2
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc2c(c1)C=C2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-nitro phthalic anhydride (3.57 g, 18.5 mmol) and freshly prepared 4-aminobenzocyclobutene 2.20 g (18.5 mmol) was heated to reflux in acetic acid (100 ml) and toluene (100 ml) under nitrogen. The water of condensation was removed continuously and azeotropically using a Dean-Stark trap. After about 17 hrs, the dark but homogeneous reaction mixture was allowed to cool to room temperature and poured into 600 ml water. The mixture was then extracted with ethyl acetate (100 ml, then 4 ×50 ml). The organic extract was washed with aq. NaHCO3 and then H2O, and finally dried over MgSO4. Immediately after the removal of hydrated MgSO4 by filtration, the filtrate was subjected to rotary evaporation to provide slightly tacky yellow-green crude product, which was redissolved in CH2Cl2. The resultant solution was filtered through a bed of silica gel (approximately 20 g) and washed with CH2Cl2 until the filtrate was colorless. The combined filtrate was again stripped on a rotary evaporator to afford yellow plates, which was collected on a fitted filter funnel, washed with petroleum ether and dried in oven under vacuum at 80° C. overnight. Yield 3.85 g (71%). Calc. for C16H10N2O4 :65.30% C; 3.42% H; 9.52% N. Found: 64.17% C; 3.29% H; 9.54% N. Mass Spectroscopy: M+ (294, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH2:19]O)=[N:9]2)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:23][CH2:19][C:10]1[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:12][N:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of N-(1-(5-fluoropyridin-3-yl)-3-(hydroxymethyl)-1H-pyrazol-4-yl)isobutyramide (0.100 g, 0.359 mmol) in dichloromethane (3.59 ml) was added thionyl chloride (0.157 ml, 2.151 mmol). The reaction was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine and concentrated to give N-(3-(chloromethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)isobutyramide (100 mg, 0.337 mmol, 94% yield) as a white solid: mp 172.0-177.0° C.; 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.80 (dt, J=9.4, 2.3 Hz, 1H), 7.42 (s, 1H), 4.77 (s, 2H), 2.63 (hept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H); ESIMS m/z 298 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N+]([CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O-])=O>CCO>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:27]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:26]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])C=Cc1ccc(O)cc1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Product: Oc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1

Procedure:
The title compound (0.09 g) was prepared from 1.22 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 856 μL of benzylamine, and 1.29 g of 4-(2-nitro-vinyl)-phenol, which was added in EtOH (12 mL). MS (ESI): exact mass calculated for C20H20N2O, 304.16; found, m/z 305.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.32 (m, 2H), 7.29-7.25 (m, 2H), 7.17-7.14 (m, 4H), 6.98 (s, 1H), 6.80-6.77 (m, 2H), 5.12 (s, 2H), 4.31 (s, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:55])([F:54])[C:27]1[N:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][CH:39]([C:42]4[C:50]5[C:45](=[CH:46][CH:47]=[C:48]([C:51]([OH:53])=O)[CH:49]=5)[NH:44][CH:43]=4)[CH2:38][CH2:37]3)[CH:34]=[CH:35][C:30]2=[N:29][N:28]=1.[CH3:56][NH:57][CH2:58][CH2:59][OH:60].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:60][CH2:59][CH2:58][N:57]([CH3:56])[C:51]([C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:34]=[CH:35][C:30]3[N:31]([C:27]([C:26]([F:25])([F:54])[F:55])=[N:28][N:29]=3)[N:32]=2)[CH2:41][CH2:40]1)=[O:53]
Reactant: CNCCO
Reactant: O=C(O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
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: CN(CCO)C(=O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
HATU (139 mg, 0.37 mmol) was added portionwise at ambient temperature to a stirred mixture of 3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylic acid (150 mg, 0.35 mmol), 2-(methylamino)ethanol (0.034 mL, 0.42 mmol) and DIPEA (0.073 mL, 0.42 mmol) in DMF (2.0 mL). The resulting solution was stirred for 2 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-hydroxyethyl)-N-methyl-3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxamide (155 mg, 91%) as a colourless solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>C(OCC)C>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[CH3:19]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)CCN1CCC(c2ccccc2)CC1
Reaction time: 8 h
Yield: 95 %

Procedure:
25.0 g of 4-phenylpiperidine (0.15 mol) are placed in 50 ml of diethyl ether and, while stirring, 15.1 g of ethyl acrylate are gradually added thereto. With a slight increase in temperature, a clear solution forms. After standing overnight at room temperature, the ether is distilled off. The oil remaining behind is the crude 3-(4-phenylpiperidino)-propionic acid ethyl ester (yield approx. 95%).