Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:10]#[N:11].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1>COCCOC.O>[C:10]([C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:25][CH2:26]1)#[N:11]
Reactant: N#CC(c1ccccn1)c1ccccn1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1N1CCN(CCC(C#N)(c2ccccn2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 0.21 g of 95% sodium amide in 2 mL of 1,2-dimethoxyethane was added dropwise a solution of 0.78 g of 2,2-bis-(2-pyridyl)acetonitrile (prepared as described in Heterocycles 1995, 40, 757) in 8 mL of 1,2-dimethoxyethane, with stirring under a nitrogen atmosphere at room temperature. After 1 h, there were added dropwise, 1.02 g of 1-(2-chloroethyl)-4-(2-methoxy-phenyl)piperazine dissolved in 4 mL of 1,2-dimethoxyethane. The resultant reaction mixture was then refluxed for 20 h, followed by cooling to room temperature, and was then poured cautiously into 40 g of ice, diluted with water, and extracted with ethyl acetate. The combined organic phases were then washed with water, dried on sodium sulphate, and then evaporated thoroughly under vacuum. The obtained crude was then purified by flash chromatography (ethyl acetate-methanol gradient from 10:0 to 9:1). The recovered fractions were then evaporated to complete dryness, affording 1.13 g of the title product (68.4%).
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:18]#[N:19].[I:20]CI>>[I:20][C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:18]#[N:19]
Reactant: CC(C)n1ncc(C#N)c1N
Reactant: ICI
Agent: CCCCCON=O
Product: CC(C)n1ncc(C#N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Amyl nitrite (13.00 g, 111.0 mmol) was added to a suspension of 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (1.77 g, 11.8 mmol) in Diiodomethane (56.0 mL, 695 mmol) at −10° C. in 30 min. The mixture was stirred for 30 min at room temperature and then heated at 100° C. for 2 hours. The mixture was then cooled and concentrated in high vacuum to give a residue which was partitioned between ethyl acetate and 5% Na2S2O5. The organic layer was washed with water, 0.1% of aq HCl, water, brine, dried and concentrated in vacuum. The residue was purified on silica column eluting with 20-30% ethyl acetate in heptane. Yield 1.68 g (55%). MS (ESI+): 262.2
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4](Cl)[N:3]=1.Cl.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C@@H:14]2[CH2:15][CH2:16][O:12][CH2:13]2)[C:5]([CH3:9])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@@H]1CCOC1
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(Cl)nc(Cl)nc1N[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.8 %

Procedure:
A mixture of 2,4,6-trichloro-5-methylpyrimidine (2 g, 10.2 mmol), (R)-tetrahydrofuran-3-amine hydrochloride (1.12 g, 9.2 mmol) and Et3N (2.1 g, 20.3 mmol) in EtOH (20 mL) was stirred at room temperature for 14 h., concentrated under vacuum and the residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/0 to 2/1) to give the (R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine (1.25 g, 53% yield) as a white solid. ESI-LCMS (m/z): 248.1 [M+1]+.
Reaction SMILES: [N:1]([C:4]1[C:5]2[S:25][CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:9]=1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]3[N:9]=[C:4]([NH2:1])[C:5]4[S:25][CH2:24][CH2:23][C:6]=4[N:7]=3)[CH2:15][CH2:14]2)=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
0.820 g (1.76 mmol) of 4-azido-2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine (IV) is placed in 10 mL of tetrahydrofuran and 3.80 mL (3.80 mmol) of lithium aluminum hydride (1M solution in tetrahydrofuran) is slowly added dropwise. The reaction mixture is stirred for 4 hours at ambient temperature. Then 0.55 mL of 1N sodium hydroxide solution and 0.50 mL of water are added, the mixture is boiled for 0.3 hours, then cooled again. It is filtered, the filtrate is dried and evaporated to dryness. The residue is extracted with ethyl acetate and 1 N hydrochloric acid. The product precipitates out, is suction filtered, then extracted with ethyl acetate and 1 N sodium hydroxide solution. The organic phase is washed with water, dried, and evaporated to dryness. The residue is stirred with petroleum ether. 0.513 g of product V (84%) is obtained as a solid (m.p. 176-178° C.). 1H NMR (400 MHz, DMSO): 7.24 (2H, d); 6.98 (2H, d); 6.30 (2H, s); 3.77-3.68 (4H, m); 3.22 (2H, t); 3.17-3.09 (4H, m); 2.99 (2H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH:7]=[CH:6][C:5]=1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])([O-])=O.C(OC1C=C([N+]([O-])=O)C=CC=1C(OCC=C)=O)C=C.N>>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH:7]=[CH:6][C:5]=1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17]
Reactant: C=CCOC(=O)c1ccc(C(=O)OCC=C)c([N+](=O)[O-])c1
Agent: C=CCOC(=O)c1ccc([N+](=O)[O-])cc1OCC=C
Agent: N
Product: C=CCOC(=O)c1ccc(C(=O)OCC=C)c(N)c1

Procedure:
The above nitro compound was reduced by the method described in example 1, for the reduction of allyl 2-allyloxy-4-nitrobenzoate, except using an aqueous solution of ammonia in place of sodium bicarbonate in the work-up, to give diallyl 2-aminobenzene-1,4-dicarboxylate.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15]Cl.C1OCCOCCOCCOCCOC1.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)CCCl
Reactant: [O-]CCCN1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CCOCCCN1CCCCC1

Procedure:
Sodium 3-piperidinopropanolate (5 mmol), 5 mmol of 3,3-dimethylbutyl chloride, a catalytic amount of tetrabutylammonium iodide, and 0.5 mmol of 15-crown-5 in 10 ml of dry dimethyl sulfoxide were refluxed for 12 hours. Water was added, and it was extracted with diethyl ether. The organic layer was purified by column chromatography on silica gel (eluent: methylene chloride/methanol (90/10), ammonia atmosphere). The solvent was removed under reduced pressure and the residue crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([C:14]([CH3:16])=O)=[CH2:13]>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[N:6]=[CH:13][CH:12]=[C:14]2[CH3:16]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: C=CC(C)=O
Product: Cc1ccnc2c([N+](=O)[O-])cc(F)cc12
Yield: 39 %

Procedure:
A Skraup reaction was run with 4-fluoro-2-nitroaniline and methyl vinyl ketone. The crude product was recrystallized multiply from benzene to obtain a 39% yield of pure 6-fluoro-4-methyl-8-nitroquinoline; mp 139°-141°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[C:20](N(OC)C)=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C#CC(=O)c2cc(Cl)cc(Cl)c2)cc1
Temperature: -40 °C

Procedure:
To a solution of 4-methoxy-1-ethynyl benzene (0.57 g, 4.27 mmol) in 20 mL of anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (3.2 mL, 5.12 mmol). After 5 minutes a solution of 3,5-dichloro-N-methoxy-N-methylbenzamide (1.0 g, 4.27 mmol) in THF (10 mL) was added to the reaction. The reaction was slowly warmed to −40° C. over 30 minutes and then quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:10 ethyl acetate-hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.09(d, J=2.0 Hz, 2H), 7.7(d, J=7.1 Hz, 2H), 7.64(t, J=1.8 Hz, 1H), 7.0(d, J=8.7 Hz, 1H), 3.91(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:30])[F:29])=[CH:13][CH:12]=1)=[O:10].[BH4-].[Na+].Cl>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:29])[F:30])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Temperature: 7.5 °C

Procedure:
Fourth, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide was prepared by reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (prepared using the procedure of Example 4) with sodium borohydride in methanol and palladium on carbon (50% wet with water) catalyst. In particular, to a 100 mL 3-neck round bottom flask were added N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (0.468 g, 1 mmol), methanol (15.0 mL), and 10% Pd—C (50% wet, 0.012 g). The reaction mixture was cooled to 5-10° C. and treated with sodium borohydride (0.127 g, 4 mmol) in four portions. The reaction mixture was acidified with conc. HCl to pH˜6, filtered and the Pd-C catalyst was washed with MeOH (˜10 ml). The combined filtrate was concentrated to a residue and slurried in excess water. The solid was filtered, washed with water (75 mL) and dried in a vacuum oven (65° C.) overnight. The dried product appeared as a yellow solid (0.310 g, 70.7%). Purity 79.57% by HPLC.
Reaction SMILES: ClC1C=CC(OC2C=CC(NC3OC(C(NC4C=CC(N5CCC(C(O)=O)CC5)=NC=4)=O)=NN=3)=CC=2)=CC=1.[Cl:39][C:40]1[CH:78]=[CH:77][C:43]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[O:56][C:55]([C:57]([NH:59][C:60]4[CH:61]=[CH:62][C:63]([N:66]5[CH2:71][CH2:70][CH:69]([CH2:72][C:73]([O:75]C)=[O:74])[CH2:68][CH2:67]5)=[N:64][CH:65]=4)=[O:58])=[N:54][N:53]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([O:44][C:45]2[CH:46]=[CH:47][C:48]([NH:51][C:52]3[O:56][C:55]([C:57]([NH:59][C:60]4[CH:61]=[CH:62][C:63]([N:66]5[CH2:71][CH2:70][CH:69]([CH2:72][C:73]([OH:75])=[O:74])[CH2:68][CH2:67]5)=[N:64][CH:65]=4)=[O:58])=[N:54][N:53]=3)=[CH:49][CH:50]=2)=[CH:77][CH:78]=1
Reactant: COC(=O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1
Agent: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nnc(Nc2ccc(Oc3ccc(Cl)cc3)cc2)o1
Product: O=C(O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1

Procedure:
Prepared by the procedure described for 1-(5-{[(5-{[4-(4-Chlorophenoxy)phenyl]amino}-1,3,4-oxadiazol-2-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxylic acid (Example 637) except starting with methyl [1-(5-{[(5-{[4-(4-chlorophenoxy)phenyl]amino}-1,3,4-oxadiazol-2-yl)carbonyl]amino}pyridin-2-yl)piperidin-4-yl]acetate (Example 640).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3c(F)cc(F)cc23)CC1

Procedure:
(8.5 mg, 54%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and phenylsulfonylchloride (10.6 mg, 0.06 mmoles) with 1M NaN(TMS)2 (60 μL, 0.06mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C:10](=[O:25])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][C:17]([CH3:23])([CH3:22])[CH:16]3[O:24][CH:15]3[C:14]=2[CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C>[NH2:1][CH:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][C:10]([NH:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:25])[CH:13]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH:16]1[OH:24]
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C2OC21
Reactant: N
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C(N)C1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
250 ml of a 25%-strength aqueous ammonia solution was added to a solution of 35 g of the N-benzyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide obtained above in 250 ml ethanol, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into 500 ml water and extracted with 250 ml dichloromethane. The organic phase was separated, dried over sodium sulfate and largely evaporated under reduced pressure. 200 ml diethyl ether was added to the remaining residue. The crystals produced after a while were removed by suction and dried on a rotary evaporator at 60° C. and 20 bar. 11 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-benzylacetamide was obtained as grey solid, which was used without further purification or characterization for the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.[N:17]([O-])=O.[Na+].[OH-].[Na+]>O.OS(O)(=O)=O.Cl>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([NH:15][NH2:17])=[C:4]([F:16])[CH:3]=1
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN1c2c(Cl)cc(F)c(NN)c2CS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine 2,2-dioxide (0.5 g, 1.89 mmol) in water (3.1 mL) and H2SO4 (1.65 mL) at 0° C. was added NaNO2 (0.13 g, 1.89 mmol) in water (0.5 mL). The reaction mixture was stirred at 0° C. for 1 h. A solution of SnCL2.H2O (0.85 g, 3.78 mmol) in conc. HCl (3.1 mL) was then added dropwise and the reaction mixture was stirred at room temperature for 12 h. Then 50% aqueous NaOH solution was added until the reaction mixture reached pH 13. The reaction mixture was extracted with ethyl acetate (200 mL) and the organic layer was washed with brine (3×50 mL) and dried (MgSO4). The solvent was removed and the title compound of Step A was isolated by flash chromatography. 1H NMR (CDCl3, 300 MHz): δ 7.04 (d,1H), 5.62 (br s,1H), 4.62 (s,2H), 3.86 (m,2H), 1.26 (t,3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13]C(=O)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>>[NH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([NH2:2])[CH:4]=1
Reactant: COc1ccc(CCNC(C)=O)cc1N
Agent: Cl
Product: COc1ccc(CCN)cc1N
Yield: 94 %

Procedure:
N-[-2-(3-amino-4-methoxyphenyl)ethyl]acetamide hydrochloride, prepared as described in Example 8 (15 g) and 175 mL of 2N HCl were heated at reflux for 6 hours. The solvent was removed by rotary evaporation, and the residue was washed with ethanol. The resulting white precipitate was filtered off and dried in vacuum, yielding 13.7 g (94%) of 5-(2-aminoethyl)-2-methoxyphenylamine (AMMPA) dihydrochloride as white crystals. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:18](OCC)C>>[CH2:1]([N:5]1[C:9]([CH:10]([OH:11])[CH3:18])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C=O)cnc1-c1ccccc1
Reactant: CCOCC
Product: CCCCn1c(C(C)O)cnc1-c1ccccc1

Procedure:
A solution of aldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatory funnel and treated with a solution of Preparation of 1-(1-Butyl)-2-phenyl-5-(1-[N-[{3,4-methylenedioxyphenylmethyl]}-N-[phenylmethyl]aminoethylimidazole) methyl lithium (1.4 M in THF, 1.5 ml). After 10 min. the solution is washed with ammonium chloride solution (1 M, 20 ml), dried (Na2SO4) and concentrated. The resulting dark oil is purified by preparative TLC (10% MeOH/CHCl3) to provide compound 107 as a colorless oil (180 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t, J=7 Hz, 3H).
Reaction SMILES: [ClH:1].[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:6]=12.[CH2:15](O)C>[Pd]>[ClH:1].[N:2]1[CH:3]=[CH:4][N:5]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=12
Reactant: CCO
Reactant: COC(=O)c1ccc2nccn2c1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)C1CCc2nccn2C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
Add 5 N hydrochloric acid (100 mL; 500.00 mmoles) and ethanol (200 mL) to a flask containing methyl imidazo[1,2-a]pyridine-6-carboxylate (4.98 g; 1.0 equiv; 28.27 mmoles) and 10% palladium on carbon (3.01 g; 0.1 equiv; 2.83 mmoles). Evacuate and backfill the reaction vessel with nitrogen (3×), then re-evacuate and backfill the reaction with hydrogen (3×). Heat the reaction mixture to 60° C. and vigorously stir under a hydrogen atmosphere for 24 hours, then evacuate and backfill the reaction vessel with nitrogen (3×) and filter the reaction mixture through Celite™, rinsing the filter cake with ethanol (100 mL). Concentrate the filtrate, add toluene (200 mL), and concentrate to dryness (repeat 2 times) to afford ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate hydrochloride (5.74 g; 88%) as a white solid. MS (m/z): 195(M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(C#N)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 4-bromomethyl-benzonitrile as described in Example 49 and isolated as a white solid (0.065 g, 46% 1H NMR (400 CDCl3) δ 3.60 (s, 1H), 8.55-8.57 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 2H), 7.46 (s, 1H), 7.26-7.31 (m, 3H), 6.90 (d, J=4 Hz, 1H), 6.11-6.16 (m, 1H), 5.41 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=415.2; Rt=1.15 min; HRMS (M+H)+=415.14.
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:29])=[N:19][C:20]([N:23]2[CH:27]=[C:26](I)[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][PH:31]([O-])([O-:35])[O:32][CH2:33][CH3:34].CCN(CC)CC>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:29])=[N:19][C:20]([N:23]2[CH:27]=[C:26]([P:31]([CH3:30])(=[O:35])[O:32][CH2:33][CH3:34])[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(-n2cc(I)cn2)nc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1cnn(-c2ncc(C(=O)NC(c3ccccc3)c3ccccc3)c(O)n2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of product of step C, compound 1-1-c, (1.2 g, 2.4 mmol), ethyl methyl-phosphite (522 mg, 4.8 mmol) and Et3N (610 mg, 6 mmol) in DMF (20 mL) was added PdCl2(dppf) (176 mg). The mixture was allowed to stir overnight at 80° C. The mixture was cooled to room temperature and diluted with water. The resulting mixture was then filtered and the filtrate was extracted with dichloromethane/methanol (5/1). The organic layer was dried over sodium sulfate and concentrated under vacuum. And the residue was purified over silica gel (dichloromethane:methanol=3/1) to provide the product, 1-1-d, (500 mg, 44%).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:28])[CH:22]=[CH:21][C:20]([S:23]([NH:26][NH2:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1>S(=O)(=O)(O)O.C(O)C>[C:17]1([CH3:28])[CH:18]=[CH:19][C:20]([S:23]([NH:26][N:27]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: O=C(C(=O)N1CCCCC1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C(C(=O)N2CCCCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of 98% sulfuric acid (121.7 g, 1.22 mol, 0.02 eq) in abs ethanol (1.0 L) was added dropwise to a stirred mixture of 1-(phenylglyoxylyl)piperidine (17.58 Kg, 80.9 mol, 1 eq), p-toluenesulfonhydrazide (16.20 Kg, 87.0 mol, 1.08 eq) and abs ethanol (50 L) at 20-30° C. The obtained mixture was stirred under reflux conditions until 1-(phenylglyoxylyl)piperidine disappeared (˜7 hours, TLC control). The mixture was stirred for 1 hour at 20-30° C. and kept overnight at 4-6° C. The precipitated solid was filtered off, washed on the filter with cold methanol and cold hexane and dried under reduced pressure to a constant weight to yield 28.25 Kg (90.6%) of 1-(phenylglyoxylyl)piperidine p-toluenesulfonylhydrazone with 99.9% purity by HPLC.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10])=[O:25]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: O=C(NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1C(F)(F)F)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-trifluoromethyl-benzoic acid.