Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]1[C:9]([CH2:8][NH2:7])=[CH:10][C:11]2[N:12]([CH:23]=[CH:24][N:25]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Yield: 52.9 %

Procedure:
A solution of [6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.07 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 30 min, then concentrated to dryness. The remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 19 mg, 0.037 mmol, 52%) as a white solid. MS: 293 [M+1]+; HPLC: AtRet=0.84.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[S:18]
Reactant: NCCNCc1cnccn1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1cnccn1

Procedure:
By the procedure of Example 40(a), treating N-(2-pyrazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:16]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:17]=[CH:18][CH:19]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:34][F:35])(=O)=O>>[F:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:16]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:17]=[CH:18][CH:19]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1cccc2ccccc12
Product: O=c1ccn(-c2cccc(OCF)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(3-Hydroxy-phenyl)-3-(2-naphthalen-1-yl-2H-pyrazol-3-yl)-1H-pyridazin-4-one (example 276) and fluoromethyl tosylate according to the method described in example 290. MS: M=413.1 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[S:6]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[F:21][C:17]1[CH:16]=[C:15]([C:7]2[S:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:29]([CH3:31])[CH3:28])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCN)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NCCCC1(c2ccccc2)SC(c2cccc(F)c2)=NN1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of 1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (9.0 mg, 0.02 mmol) and acetone (20 mg, 0.40 mmol) in acetonitrile (0.5 mL) was stirred at room temperature for 1 hour. To the mixture was added sodium triacetoxyborohydride (33 mg, 0.20 mmol). After stirring at room temperature for 16 hours, more acetone (50 μL) and sodium triacetoxyborohydride (14 mg) was added. The reaction mixture was heated to 45° C. for 40 hours and then diluted with 10% Na2CO3 (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2% triethylamine, 40% ethyl acetate in hexanes) to provide the product (5.4 mg, 50%) as pale yellow film. MS ESI (+) m/z 428 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=7 Hz), 7.37 (m, 4H), 7.27 (m, 1H), 7.14 (m, 1H), 3.50 (m, 1H), 3.21 (m, 1H), 2.80 (m, 1H), 2.73 (m, 2H), 2.39 (m, 1H), 1.95 (m, 1H), 1.56 (m, 1H), 1.19 (d, 3H, J=6 Hz), 1.17 (d, 3H, J=6 Hz), 1.05 (d, 6H, J=6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[CH2:14]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[O:8][CH:14]([CH2:13][C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[C:5]=2[CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCCC
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)CC1OC(=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-methoxybenzoic acid (1.52 g, 10.0 mmol), palladium (II) acetate (0.56 g, 2.5 mmol), copper (II) acetate monohydrate (0.499 g, 2.5 mmol) and 4 Å molecular sieves (1.75 g) in DMF (40 ml) was stirred at room temperature for 5 minutes. Butyl acrylate was add (2.57 g, 20.0 mmol), and the resulting mixture was heated at 120° C. for 25 hours and then at 140° C. for 9 hours. Upon cooling the mixture was filtered and partitioned between dilute HCl aqueous solution and EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution, water, brine, then dried with anhydrous Na2SO4 and rotary evaporated to a brown oil. The oil was triturated with hexane and the remaining oil was chromatographed through silica gel column (20% to 30% EtOAc/Hexane gradient) to give the desired product contaminated with 4-methoxybenzoic acid. The mixture was dissolved in EtOAc and washed with saturated NaHCO3 aqueous solution, brine, dried with anhydrous Na2SO4. Removal of the solvent yielded butyl (6-methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetate as a light yellow oil (0.26 g, 9%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[N:16]=[C:17]([CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[C:20]=3[N:21]=2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])O.[Na+]>ClCCl>[N:27]1([CH2:26][C:17]2[N:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[C:20]3[N:21]=[C:13]([C:9]4[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][CH:10]=4)[O:14][C:15]=3[N:16]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: CCCOc1nc(CN2CCOCC2)nc2oc(-c3cccc(OC)c3)nc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1nc(CN2CCOCC2)nc2oc(-c3cccc(O)c3)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
1.25 ml of a 1 M solution of boron tribromide in dichloromethane were slowly added to a solution of 160 mg of 2-(3-methoxy-phenyl)-5-morpholin-4-ylmethyl-7-propoxy-oxazolo[5,4-d]pyrimidine in 5 ml of dichloromethane at 0° C. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 1 h. The mixture was cautiously neutralized with a saturated solution of sodium hydrogencarbonate. The organic layer was separated and the aqueous layer extracted two times with dichloromethane. The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (method HPLC1) to give 23 mg of the title compound in the form of 3-(5-morpholin-4-ylmethyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)phenol trifluoroacetic acid salt.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1>C1COCC1>[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH3:3])[CH:9]=1
Reactant: CI
Reactant: COc1ccc2c(CCBr)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(CCBr)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with NaH (110 mg, 4.60 mmol), MeI (0.39 mL, 6.13 mmol) and THF (1.5 mL). The resulting grey suspension was stirred at rt for 5 min, then a solution of 3-(2-Bromo-ethyl)-6-methoxy-1H-indole (156 mg, 0.61 mmol) in THF (2.5 mL) was added dropwise. After stirring for 18 h at rt, the reaction mixture was concentrated, redissolved in DCM and washed with H2O (3×). The org. layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the title compound as an yellow oil which was used as such in the next step. LC-MS conditions B: tR=0.94 min, [M+H]+=no ionization.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:3]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:3]1
Reactant: Nc1nnc(Br)s1
Reactant: CC1CCN(Cc2cccc(OCCCN)c2)C1
Product: CC1CCN(Cc2cccc(OCCCNc3nnc(N)s3)c2)C1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(3-methylpyrrolidin-1-yl) methyl]phenoxy]propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:19][C:20]([F:31])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-trifluoromethoxyphenylboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (17%, brown oil).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1>[OH-].[Na+].[Ru]>[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:7]([OH:9])=[O:8])[CH2:10][CH2:11]1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Ru]
Agent: [Na+]
Agent: [OH-]
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
30 g of p-aminomethylbenzoic acid, 3 g of 5% ruthenium supported on activated carbon and 100 ml of an aqueous sodium hydroxide solution as a solvent under the conditions shown in Table 4 below were charged in an autoclave and then reacted at a temperature of 80° C, 100° C, and 150° C, respectively, under an initial hydrogen pressure of 150 kg/cm2 to obtain trans-4-aminomethylcyclohexane-1-carboxylic acid in each case. The reaction product thus obtained was in the form of the sodium salt and was converted into the free acid using an ion-exchange resin.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:32])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:34]([NH2:36])=[O:35])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C1COCC1.CN(C1C=CN=CC=1)C>[C:44]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:32])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:34]([NH2:36])=[O:35])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3])(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nn(-c2ccc(S(N)(=O)=O)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirring solution of 1-[4-(aminosulfonyl)phenyl]-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (2967 mg, 5.7 mmol) in THF (120 mL) was added DMAP (348 mg, 2.8 mmol), then tri-ethyl amine (0.95 mL, 6.8 mmol), followed by acetic anhydride (1.62 mL, 17.1 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. To the residue was added 5% aq. NaHCO3 (100 mL). All compounds were dissolved. The aq. Layer was washed with EA (100 mL×2), CH2Cl2 (100 mL). The aq. layer was separated. To the aq. Layer was added 1N HCl to pH=6. A white precipitate was formed. It was filtered and washed with ether to give a white solid. The solid was dried under reduced pressure at 45° C. to give 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (2255.4 mg, 70%).
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:24][P:25](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].O>ClCCl>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][P:25]([CH3:24])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Reactant: CP(=O)(Cl)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CP(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)c1ccccc1
Reaction time: 1 h
Yield: 28.7 %

Procedure:
A solution of 20 mg of 3-styryl-1H-indazol-5-ol, 5.76 mg of imidazole and 20.7 mg of methylphenylphosphinic chloride in 5 ml of dichloromethane is stirred at ambient temperature. After stirring for approximately one hour, 5.76 mg of imidazole and 20.7 mg of methylphenylphosphinic chloride are added. The suspension is stirred at ambient temperature for approximately 18 hours. 10 mg of imidazole and 70 mg of methylphenylphosphinic chloride are added. After 30 hours at ambient temperature, the reaction medium is treated with 10 ml of distilled water. The aqueous phase is extracted with 2×10 ml of dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure in a rotary evaporator. The reaction crude is purified by preparative LC/MS to obtain 9.1 mg of methylphenylphosphinic acid 3-((E)-styryl)-1H-indazol-5-yl ester.
Reaction SMILES: II.[C:3]([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH2:19]I)[C:16](=[O:21])[O:15][CH2:14][C@H:13]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12](=[O:30])[O:11][C@H:10]1[CH3:31])(=[O:7])[CH:4]([CH3:6])[CH3:5].F[C:33]1[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O.[Zn].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:3]([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH2:19][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16](=[O:21])[O:15][CH2:14][C@H:13]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12](=[O:30])[O:11][C@H:10]1[CH3:31])(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCI
Reactant: Fc1ccc(I)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: II
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCc1ccccc1
Temperature: 40 °C
Reaction time: 0.03 h
Yield: 50.7 %

Procedure:
To an oven-dried flask containing a magnetic stir bar was added freshly ground zinc dust (149 mg, 2.28 mmol) and a small volume of DMF (100 μL) was added to just cover the dust. Iodine (57 mg, 0.23 mmol) was added and the mixture stirred for 2 min and then warmed to 40° C. A solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-iodoethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (200 mg, 0.38 mmol) in DMF (1 mL) was added slowly at 40° C. After 15 min, the reaction mixture was cooled to ambient temperature (about 22° C.), and a solution of Pd((o-tol)3P)2Cl2 (7.5 mg, 0.01 mmol) and 1-fluoro-4-iodobenzene (58 uL, 0.49 mmol) in DMF (900 μL) was added to the reaction and the reaction was warmed back to 40° C. and stirring continued for 2.5 h. The mixture was cooled, diluted with EtOAc (2 mL) and filtered through a 0.45 μm fritted filter disc. The filtrate was diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, hexanes/EtOAc gradient) gave the title compound (92 mg, 51%) as a white glassy solid: 1H NMR (300 MHz, CDCl3) δ 7.31-7.14 (m, 3H), 7.14-7.04 (m, 2H), 5.46-5.15 (m, 2H), 5.06 (t, J=9.9 Hz, 1H), 4.91-4.72 (m, 2H), 3.61 (s, 1H), 2.76-2.48 (m, 3H), 2.40 (dt, J=13.8, 8.2 Hz, 1H), 2.17-1.99 (m, 1H), 1.73-1.52 (m, 1H), 1.45 (s, 9H), 1.25 (d, J=6.3 Hz, 3H), 1.16 (d, J=7.0 Hz, 6H); ESIMS m/z 500 ([M+Na]+).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=4)[N:25]=3)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[F:32][C:29]([F:30])([F:31])[C:26]1[N:24]2[N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([O:13][C:12]4[CH:33]=[CH:34][C:9]([OH:8])=[CH:10][CH:11]=4)[CH2:19][CH2:18]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(Oc4ccc(OCc5ccccc5)cc4)CC3)nn12
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
10% Palladium on carbon (0.574 g, 0.54 mmol) was added to 6-[4-[4-(benzyloxy)phenoxy]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.53 g, 5.39 mmol) in MeOH (30 mL) under an atmosphere of hydrogen. The resulting suspension was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]phenol (1.760 g, 86%) as a gum which crystallised on standing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[CH:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[CH:16]([NH2:18])[CH3:17]
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1nc2ncccc2n1-c1ccccn1
Reaction time: 0.83 h

Procedure:
To a mixture of tert-butyl 1-(1-(pyridin-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethylcarbamate (0.516 g, 1.520 mmol) in DCM (10.14 mL) was added TFA (10.14 mL, 132 mmol) dropwise at rt with stirring. After 50 min, the mixture was concentrated in vacuo and co-evaporated with triethylamine and MeOH. The neutralized crude mixture was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide 1-(1-(pyridin-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethanamine as brown syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.76 (1H, m), 8.49 (1H, dd, J=4.7, 1.6 Hz), 8.19 (1H, td, J=7.7, 2.0 Hz), 7.79-7.92 (2H, m), 7.63 (1H, ddd, J=7.6, 4.8, 0.9 Hz), 7.32 (1H, dd, J=8.1, 4.8 Hz), 4.47 (1H, q, J=6.7 Hz), 1.45 (3H, d, J=6.8 Hz); LC-MS (ESI) m/z 240.1 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (105 mg, 92%), MS (ISP) m/z=457.4 [(M+H)+], mp 233° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1/[CH:5]=[C:12]1/[C:11](=[O:16])[CH2:15][CH2:14][CH2:13]/1
Reactant: O=C1CCCC1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1/C=C1\CCCC1=O

Procedure:
The procedure was similar to that in Example 4 by reacting 2-methoxybenzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-[(2-methoxy) benzylidene] cyclopentanone. The melting popint of this intermediate compound was determined to be 80°-82° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 167°-169° C.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH:2]=[CH2:3].[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Pt].C1(C)C=CC=CC=1>[Cl:10][Si:11]([Cl:13])([Cl:12])[CH2:3][CH2:2][CH2:1][C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: C=CCc1ccc(C)s1
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1ccc(CCC[Si](Cl)(Cl)Cl)s1

Procedure:
The hydrosilylation reaction of Example 1 was repeated using 4.5 g of 2-allyl-5-methylthiophene in place of 2-allylthiophene, 2.5 g of anhydrous toluene, 5.0 g of trichlorosilane, and 50 mg of Platinum Catalyst. 2-(3-Trichlorosilylpropyl)-5-methylthiophene was obtained as a colorless liquid: 1H NMR (CDCl3) δ 6.60 (m, 2H); 2.88 (t, 2H, J=7.2 Hz); 2.47 (s, 3H); 1.95 (m, 2H); 1.47 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:23])[O:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:25]([O:16][C:13]1[CH:14]=[C:15]2[C:5]3([O:4][N:3]([CH3:23])[C:2]([NH2:1])=[N:6]3)[CH2:7][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:9][C:10]2=[CH:11][CH:12]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(O)cc32)N=C1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(OCc4ccccc4)cc32)N=C1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.5 %

Procedure:
A mixture of 3′ amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazol)-6-ol (30 mg, 0.096 mmol), (bromomethyl)benzene (21.45 mg, 0.125 mmol) and K2CO3 (16 mg, 0.115 mmol) was dissolved in acetone, then the mixture was stirred at room temperature for 24 hours. The mixture was filtrated and concentrated. The residue was purified by preparative HPLC to give 6-(benzyloxy)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]3′-amine (140) (0.95 mg, 3%). 1H-NMR (MeOD): 7.32-7.56 (m, 10H), 6.91-7.23 (m, 3H), 5.12 (d, 2H), 5.23 (t, 2H), 3.31 (s, 3H) 2.73 (m, 1H), 2.32 (m, 1H);
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][NH:29][CH2:28][CH2:27][NH:26]2)=[N:21]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:29]4[CH2:28][CH2:27][NH:26][CH:25]([C:22]5[CH:23]=[CH:24][NH:20][N:21]=5)[CH2:30]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1cc(C2CNCCN2)n[nH]1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4cc[nH]n4)C3)c(F)cc2c1=O
Temperature: 130 °C
Yield: 19.7 %

Procedure:
A mixture of 703 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.14 g of 2-(1H-pyrazol-3-yl)piperazine and 5 ml of pyridine was heated in a pressure bottle at 130° C. for 24 hours. It was allowed to cool at room temperature, then cooled to 0° C., the pyridine removed and the crude product purified by flash chromatography on silica gel, giving 195 mg of the desired product.