Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:24]([O:28][C:29](=[O:30])[NH:31][C@H:32]([C:33](=[O:34])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=1)[CH3:36])([CH3:25])([CH3:26])[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1cccc(Nc2ccccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
Triethylamine (0.35 mL, 2.59 mmol) was added to a mixture of 3-(2-aminophenylamino)benzonitrile (177 mg, 0.85 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (190 mg, 1.02 mmol), HOAt (140 mg, 1.02 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (190 mg, 1.02 mmol) in anhydrous DCM (10 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) to afford the title compound as a yellow oil (290 mg, 90%). Material still impure, taken forward in the next step without further purification. LCMS (Method J): RT 3.54 min [M+H]+ 380.8
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[OH:15].[H][H]>C1COCC1.[Ni]>[NH2:12][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]([F:1])=[C:3]([OH:15])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(O)c(F)cc1C(F)(F)F

Procedure:
Raney-Ni (0.5 g) was added to a solution of 2-fluoro-5-nitro-4-(trifluoromethyl)phenol obtained in Reference Example 17 (0.5 g) in THF (5 ml), and the mixture was stirred for 2 hours in a hydrogen atmosphere. The catalyst was removed by filtration and the catalyst was washed with THF. The combined filtrate and washings were diluted with THF to obtain a solution of 5-amino-2-fluoro-4-(trifluoromethyl)phenol in THF (50 ml).
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([O-:5])=[O:4]>S(=O)(=O)(O)O>[I:1][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: II
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 97987.5 %

Procedure:
To a stirred solution of iodine (137.95 g, 0.5436 mmol) in filming sulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g, 0.3866 mmol) at room temperature. The reaction mixture was slowly heated to 85° C. overs 2 hours and stirred at the same temperature for another 12 hours. The reaction mixture was cooled to room temperature and poured into ice, and the aqueous solution was extracted with dichloromethane. The organic phase was separated and washed with water, 2.0 M solution of Na2S2O3 and brine, and then dried over Na2SO4. Solvent was removed under reduced pressure to yield 3-iodo-5-nitrobenzoic acid as slight yellow solid 111 g, yield 98%. MS (M+H)=294.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:12])C>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][OH:12])=[N:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)[n+]([O-])c1
Product: Cc1ccc(CO)nc1
Temperature: 25 °C
Yield: 80 %

Procedure:
2,5-Dimethylpyridine 1-oxide (2.5 g, 20.3 mmol) was added to acetic anhydride (8.2 mL) at 100° C. over a period of 30 min. Then the mixture was refluxed 1 h. The mixture was cooled to room temperature and carefully quenched with ethanol (11 mL). The reaction mixture was concentrated. The residue was treated with 1N HCl (6 mL) and refluxed 1 h. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give (5-methylpyridin-2-yl)methanol (2 g, 80.0% yield) as a light yellow oil. LCMS MH+ 124.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28](Cl)=[O:29])=[CH:10][CH:9]=1.O>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:29])=[CH:10][CH:9]=1
Reactant: O=C(Cl)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: O=C(COCc1nc2ccccn2c1C#Cc1ccc(F)cc1)N1CCOCC1
Yield: 58 %

Procedure:
0.806 ml (9.25 mmol) of morpholine were solubilised in 4 ml of dichloromethane with magnetic stirring, a solution of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetyl chloride in 4 ml of dichloromethane was added and then the mixture was added at r.t. for 1 h before being treated with 10 ml of water. The aqueous phase was extracted with 2×5 ml of dichloromethane. The combined organic phases were washed with 5 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.211 g (yield=58%) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)-1-morpholino ethanone were obtained as a pale yellow solid. LC-MS: m/z=394 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.8 Hz, 1H), 7.74 (dd, J=8.7, 5.5 Hz, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.50-7.39 (m, 1H), 7.33 (t, J=8.9 Hz, 2H), 7.12 (t, J=6.8 Hz, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.55-3.46 (m, 4H), 3.39 (s, 4H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:29])[CH3:28])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)C=CN=C1.N[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[CH:27]([N:12]1[C:10]2=[N:11][C:6]([NH:1][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:35][CH:36]=3)=[N:7][CH:8]=[C:9]2[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13]1=[O:26])([CH3:29])[CH3:28]
Reactant: COc1ccc(Cn2c(=O)c3cnc(-n4ccnc4)nc3n(C(C)C)c2=O)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2c(=O)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc3n(C(C)C)c2=O)cc1
Temperature: 180 °C
Yield: 57.7 %

Procedure:
A mixture of 700 mg (1.78 mmol) of 7-(imidazol-1-yl)-1-isopropyl-3-(4-methoxybenzyl)-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 1.02 g (5.35 mmol) of 1-(4-aminophenyl)-4-methylpiperazine is heated at 180° C. for 2 hours. The reaction mixture is cooled, dissolved into chloroform, and chromatographed on silica eluting with 5:95 methanol/chloroform. The resulting material is crystallized from methanol/water to give 530 mg (58%) of the title compound: mp 215-216° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]([OH:15])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC(CCCCc1ccccc1)Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(CCCCc1ccccc1)Sc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of t-butyl 7-phenyl-3-phenylsulfanylheptanoate (1.8 g; 6.5 mmol) in CH2Cl2 (20 mL) is slowly added trifluoroacetic acid (6 mL). The reaction is stirred 5 hours and concentrated in vacuo to yield 7-phenyl-3-phenylsulfanylheptanoic acid which is used directly in Step I.
Reaction SMILES: C([NH:8][C@H:9]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Br:21])=[CH:20][C:14]=2[N:13]=1)[CH2:10][OH:11])(OC(C)(C)C)=O.Cl>C(OCC)(=O)C.O1CCOCC1>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([C@@H:9]([NH2:8])[CH2:10][OH:11])=[N:13][C:14]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.00 g (5.62 mmol) (1R)—N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine in 40 ml of ethyl acetate are combined with 8.0 ml 4-molar hydrochloric acid in dioxane while cooling in the ice bath and stirred for 16 hours at ambient temperature. The reaction mixture is evaporated down and the resulting precipitate is filtered off.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12](Cl)=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.O.[NH2:16][NH2:17]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([NH:16][NH2:17])=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: NN
Reactant: O=C(Cl)C1(c2cccs2)CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)C1(c2cccs2)CCOCC1

Procedure:
4-(2-Thienyl)tetrahydropyran-4-carboxylic acid was reacted with thionyl chloride and a catalytic amount of DMF in methylene chloride under heating to obtain 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride. A THF solution of 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride was added dropwise to a THF solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 4-(2-thienyl)tetrahydropyran-4-carbohydrazide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7](=[CH:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[CH2:16][O:15][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7](=[CH:13][CH3:14])[CH2:6]2
Reactant: CC=C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CC=C1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O

Procedure:
[(6,7-Dichloro-2-ethylidene-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid (U.S. Pat. No. 3,704,314) (30.1 gm., 0.1 mole) is dissolved in methanol (150 ml.) and conc. sulfuric acid (0.5 ml.) added. The mixture is stirred and refluxed for 2 hours. The solvent is removed in vacuo by evaporation on a rotary evaporator and the residue dissolved in ethyl ether, washed with water and dried over sodium sulfate. The ether is removed by evaporation in vacuo in a rotary evaporator to give methyl[(6,7-dichloro-2-ethylidene-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH2:16]C)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O-:19].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:18][O:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)Nc1ccc2c(Cl)nccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)Nc1ccc2c(OC)nccc2c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
In dimethyl sulfoxide (45 ml) was dissolved 2.27 g of 1-chloro-6-ethoxycarbonylaminoisoquinoline (Preparation Example 41). To the mixture was added 28% sodium methoxide solution (8.7 ml), followed by heating under stirring at 110° C. for 1.5 hours. After cooling to room temperature as it was, an aqueous saturated ammonium chloride was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (1.75 g, 84%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30]Cl)=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30][NH:42][O:40][CH3:41])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCl)n2CC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Reaction time: 40 h
Yield: 36.1 %

Procedure:
7-(Benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.3 g, 5.26 mmol) and triethylamine (1.6 g, 15.78 mmol) were added to a solution of methoxylamine hydrochloride (0.88 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (11 mL). The reaction was heated with stirring for 40 hours at 50° C., allowed to cool to ambient temperature, and partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with another portion of dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using a HORIZON HPFC system equipped with a FLASH 40+M silica cartridge eluting with dichloromethane:methanol in a gradient from 100:0 to 90:10. The resulting product (1.0 g) was recrystallized from acetonitrile, and the crystals were isolated by filtration, washed with acetonitrile, and dried overnight in a vacuum oven at 65° C. to provide 0.85 g of 7-(benzyloxy)-2-[(methoxyamino)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow, crystalline solid, mp 190-193° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:17](=[O:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][CH:12]=1)[CH2:2]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NC1CN2CCC1CC2
Yield: 44 %

Procedure:
Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine (200 mg, 1.00 mmol) and biphenyl-4-yl-acetic acid gave the title compound as a white solid (140 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 7.56 (t, J=8.0 Hz, 4H), 7.29-7.41 (m, 5H), 4.19 (br s, 1H), 3.70 (t, J=7.2 Hz, 1H), 3.58 (s, 2H), 3.24-3.31 (m, 5H), 3.12-3.19 (m, 1H), 2.16-2.17 (m, 2H), 1.95-1.98 (m, 2H), 1.82 (br s, 1H) ppm. 13C NMR (400 MHz, CD3OD) δ 173.1, 140.8, 140.0, 134.7, 129.4, 128.7, 126.9, 52.3, 46.4, 45.9, 44.3, 41.9, 24.4, 21.5, 17.1 ppm. Purity: 93.9% HPLCMS (210 nm); retention time 2.87 min; (M+1) 321.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:21]([N:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15](=[O:16])[NH2:34])[CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Reactant: N
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)C(CCc2cccc(C(N)=O)c2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
A mixture of 85 mg (0.21 mmol) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid, 81 mg (0.42 mmol) of EDC, 57 mg (0.42 mmol), and 2.6 mg (0.021 mmol) of DMAP is stirred in DMF for 2 h at rt. After cooling to −40° C. ˜0.2 mL of NH3 is condensed into the mixture. The resulting solution is sealed and stirred at rt for 10 h. The mixture is concentrated and purified by preparatory TLC (10% MeOH in CH2Cl2) to provide 66 mg (78%) of [3-(3-carbamoyl-phenyl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[CH:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COc1ncc(Cl)cc1NC1CN(C(=O)OC(C)(C)C)C1
Reactant: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2ccnc(F)c2)cc1NC1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of tert-butyl 3-((5-chloro-2-methoxypyridin-3-yl)amino)azetidine-1-carboxylate (2.00 g, 6.37 mmol) in dioxane/water (5:1, 38 mL) was added 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.85 g 8.29 mmol), Xphos-Pd-G2 (125 mg, 0.159 mmol), and K3PO4 (2.90 g, 13.7 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 1 h. After cooling to RT, the reaction mixture was filtered and washed with ethyl acetate (100 mL). The organic layer was washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to obtain 2.4 g of tert-butyl 3-((2′-fluoro-6-methoxy-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate as a white yellow solid (100%): 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.3 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.24 (dt, J=5.5, 1.6 Hz, 1H), 6.96 (t, J=1.5 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 4.60 (d, J=6.5 Hz, 1H), 4.29 (dd, J=8.9, 7.1 Hz, 2H), 4.19 (qd, J=6.7, 5.7, 1.9 Hz, 1H), 3.99 (s, 3H), 3.75 (dd, J=9.1, 4.7 Hz, 2H), 1.38 (s, 9H); MS (ES) m/z 375 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:14]2)=[N:11][CH:12]=1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[O:20]=[C:19]1[C@@:15]2([CH2:27][CH2:28][CH2:29][N:13]([C:10]3[N:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][CH:9]=3)[CH2:14]2)[CH2:16][CH2:17][N:18]1[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Reaction time: 1 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5S)-7-(5-aminopyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one (15.8 mg, 0.0000478 mol), N,N-diisopropylethylamine (27 μL, 0.00016 mol) and methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 1 h. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 389.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10]Cl)=[CH:4][N:3]=1.[CH3:12][OH:13]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10][O:13][CH3:12])=[CH:4][N:3]=1
Reactant: N#Cc1nc(CCl)cnc1N
Reactant: CO
Product: COCc1cnc(N)c(C#N)n1

Procedure:
2-Amino-3-cyano-5-chloromethyl pyrazine (0.95 g) was reacted with a large excess of dry methanol, under nitrogen, at reflux, for about 18 hours. The resulting reaction mixture was filtered and the filtrate was taken to dryness by evaporation. A yellow residue was collected and extracted twice with boiling methylene chloride. These extracts were filtered and the solvent evaporated to give 2-amino-3-cyano-5-methoxymethylpyrazine which was then treated with an excess of guanidine in methanol according to the method of Taylor (J. Org. Chem., 2817, 38, (1973)). Most of the product of this reaction precipitated and was collected by filtration. The filtrate was mixed with silica gel, stripped of solvent by evaporation, and the residue was placed on a silica gel column. This column was eluted with methanol (5%) in ethylacetate to yield a second crop of product which was added to that previously collected. The combined crops were recrystallized from methanol to yield 2,4-diamino-6-methoxymethyl pteridine (mp 248°-251°).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.BrC1C=C(C)C=CN=1.[F:24][C:25]([F:53])([F:52])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:50](Cl)=[N:49][CH:48]=[CH:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(O)(C)(C)C>[F:53][C:25]([F:24])([F:52])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:50]([O:15][CH2:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([Br:7])[CH:13]=4)=[N:49][CH:48]=[CH:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: OCc1ccnc(Br)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: Cc1ccnc(Br)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium t-butoxide (0.073 g, 0.66 mmol) and t-butanol (0.5 mL) was added dropwise with stirring (2-bromo-pyridin-4-yl)-methanol (0.082 g, 0.44 mmol, prepared in the similar fashion as Example 16a from 2-Bromo-4-methyl-pyridine), followed by 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (0.100 g, 0.22 mmol; prepared in Example 16b). The mixture was stirred at room temperature overnight. LC/MS analysis indicated formation of the desired product. The mixture was concentrated in vacuo, and the crude product was purified on preparative HPLC to afford N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-bromopyridin-4-yl)methyl]-oxy}pyrazin-2-yl)piperazine-1-carboxamide (5 mg). 1H NMR (CDCl3) 8.40 (s, 1H), 7.95 (s, 2H), 7.8 (s, 1H), 7.6 (s, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 6.62 (s, 1H), 5.4 (s, 2H), 3.6 (m, 4H), 1.6 (m, 4H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([NH:16][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: Oc1cccc(Cl)n1
Solvent: CCO
Product: Oc1cccc(NCc2ccccc2)n1
Temperature: 25 °C

Procedure:
6-Chloro-2-pyridinol (6.1 g, 0.047 mole) and 10.1 g (0.094 mole) of benzylamine were mixed and heated in an oil bath at 120°-130° for 48 hours. The liquid mass gradually solidified. The cooled mixture was boiled with 100 ml of 50% aqueous ethanol and cooled to 25° C.; the supernatant was decanted from a gum (which was saved), cooled to 5° C., decanted from black tar, and diluted with 50 ml of water. A grey, granular solid, m.p. 158°-162° C., crystallized. An additional quantity of the same material was recovered as follows: The retained gum was digested with 50 ml of hot 95% ethanol until it was solid; the mixture was cooled to 5° C., the solid removed, and the filtrate diluted with water. The total yield of the title compound was 2.4 g (25%). Recrystallization from benzene-n-hexane raised the m.p. to 164°-165°. 1H nmr (CDCl3 +D2O, 100 MHz), δ4.28 (s, 2H, CH2), 5.28 (d, 1H, H5, J=8 Hz), 5.50 (d, 1H, H3, J=9 Hz), 7.17 (t, 1H, H4, J=8 Hz), 7.30 (s, 5H, C6H5).