Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:16])[CH:10]=[CH:11]2)=[N:6]1.Cl>CC(C)=O>[O:2]=[CH:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:16])[CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(Cn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1

Procedure:
To a stirred solution of 1-[2-(2,2-dimethoxyethyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea (1.5 g, 3.47 mmol) in acetone (250 mL) was added 2N aqueous HCl (10 mL) and the reaction was heated to reflux for 72 hours. The mixture was allowed to cool and was concentrated under reduced pressure to a volume of 30 mL. Ethyl acetate (300 mL) was added to the slurry with stirring and the mixture was filtered. The solid was washed with additional ethyl acetate (10 mL) and air-dried to provide 1-[2-(2-oxo-ethyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.38 (s, 2 H), 6.98 (m, 5 H), 7.09 (m, 1 H), 7.36 (m, 2 H), 7.49 (m, 2 H), 7.65 (m, 1 H), 7.87 (s, 1 H), 8.27 (s, 1 H), 8.87 (m, 2 H), 9.66 (s, 1 H); MS (ESI) 385 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:25][CH3:26])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:36][C:37]([F:55])([F:54])[C:38]1[CH:39]=[C:40]([C:48]([CH3:53])([CH3:52])[C:49](Cl)=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([N:25]([CH3:26])[C:49](=[O:50])[C:48]([C:40]3[CH:39]=[C:38]([C:37]([F:55])([F:54])[F:36])[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=3)([CH3:53])[CH3:52])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc2c1cnn2Cc1ccccc1
Temperature: 40 °C
Yield: 83 %

Procedure:
To a solution of [1-benzyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-methyl-amine (2.125 g, 6.13 mmol) in CH2Cl2 (30 mL) was added iPr2NEt (2.14 mL, 12.3 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 2.93 g, 9.20 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 3.2 g (83%) of the title compound as a white foam. ES-MS m/e: 629.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH:21]1([CH2:24][NH:25][CH2:26][C:27]2[NH:28][C:29](=[O:38])[C:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][N:25]([CH2:26][C:27]2[NH:28][C:29](=[O:38])[C:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22]1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1CCCCC2
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)CCCCC4)CC3CC3)CC2)cc1
Yield: 7.9 %

Procedure:
The title compound (18 mg, 8% yield) was prepared following the general procedures of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (124 mg, 0.45 mmol) and 2-((cyclopropylmethylamino)methyl)-6,7,8,9-tetrahydro-3H-cyclohepta[d]pyrimidin-4(5H)-one (104 mg, 0.45 mmol). 1H NMR (400 MHz, CDC3) δ 7.85 (d, J=8.5 Hz, 2H), 6.70-6.97 (m, 2H), 4.41 (s, 1H), 4.34 (s, 1H), 3.68-3.91 (m, 3H), 3.41 (s, 3H), 3.33 (d, J=7.0 Hz, 1H), 3.07-3.29 (m, 4H), 2.91 (d, J=10.5 Hz, 2H), 2.57-2.79 (m, 4H), 2.50 (br. s., 1H), 2.12-2.37 (m, 1H), 2.04 (d, J=14.1 Hz, 2H), 1.76 (d, J=5.0 Hz, 4H), 1.36-1.65 (m, 1H), 0.75-1.04 (m, 1H), 0.46 (d, J=7.5 Hz, 1H), 0.26-0.41 (m, 1H), 0.15-0.26 (m, 1H), 0.12 (d, J=4.5 Hz, 1H). HRMS calculated for C23H38N4O4 507.2971. found (ESI, [M+H]+), 507.2975. Retention time=3.54.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:33])[N:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:32])[CH:17]([NH:24]C(=O)OC(C)(C)C)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:12][CH2:11]3)[CH2:9][C:5]2=[CH:4][N:3]=1.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[NH2:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][C:5]3=[CH:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]2=[O:33])[CH2:11][CH2:12]1)=[O:32]
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)CC1)C2
Agent: Cl
Solvent: CCO
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2

Procedure:
tert-Butyl 2-(4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)-2-oxo-1-phenylethylcarbamate (13 g) obtained in Example 50a) was dissolved in concentrated hydrochloric acid (30 ml) and ethanol (30 ml). The reaction mixture was mixed at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. Water in the residue was removed by azeotropy with ethanol to obtain the title compound as pale yellow powder (12 g, quantitative).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(OC(F)(F)F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-trifluoromethoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.96 (d, J=13 Hz, 2H), 2.12 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.40 (s, 2H), 3.50 (s, 2H), 3.60 (s, 4H), 4.40 (s, 1H), 7.45-7.51 (m, 1H), 7.56-7.62 (m, 1H), 7.74 (s, 1H), 7.82-7.87 (m, 1H); MS (APCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([O:62][C:63]4[N:68]=[CH:67][C:66](O)=[CH:65][CH:64]=4)[CH:60]=3)[N:55]=[CH:54][N:53]=2)=[N:47]1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([O:62][C:63]4[N:68]=[CH:67][C:66]([O:1][CH2:2][CH:3]5[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]5)=[CH:65][CH:64]=4)[CH:60]=3)[N:55]=[CH:54][N:53]=2)=[N:47]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCC5CN(C(=O)OC(C)(C)C)C5)cn4)cc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (110 mg, 0.60 mmol), triphenyl phosphine (160 mg, 0.60 mmol) and diethyl azodicarboxylate (0.095 mmol, 0.60 mmol) were added to a tetrahydrofuran solution (3 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (100 mg, 0.30 mmol) obtained in Example 6-3), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 3-({[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}methyl)azetidine-1-carboxylate (136 mg, yield: 90%) as a pale yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=C1CNCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])nc2)CCN1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube were added 5-bromo-2-nitropyridine 141-1 (1.01 g, 5 mmol), piperazin-2-one 141-2 (0.6 g, 6 mmol), DIEA (1.8 mL, 18 mmol) and DMSO (6 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled down to room temperature. DIEA was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give 4-(6-nitropyridin-3-yl)piperazin-2-one 141-3 as light yellow solid. MS m/z 223.2 (M+1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Solvent: O
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 ml of the dried particles from Example 2 of size 10 μm were dispersed in a solution containing 150 ml water, 20 g resorcinol and 60 g formaldehyde solution (37%). The resulting mixture was kept at 70° C. for 1.5 hours under stirring. After cooling to ambient temperature the particles were separated from the reaction mixture and washed with water on a sieve of mesh size 37 μm. The particles had a diameter of 68 μm in water and shrank somewhat in air to 61 μm diameter.
Reaction SMILES: BrBr.[C:3]([C:5]([C:22]#[N:23])=[N:6][C:7]([CH3:21])=[C:8]([N:15]1CCOCC1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4].N>C(Cl)Cl>[C:3]([C:5]1[C:22]([NH2:23])=[N:15][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([CH3:21])[N:6]=1)#[N:4]
Reactant: CC(N=C(C#N)C#N)=C(c1ccccc1)N1CCOCC1
Agent: BrBr
Agent: N
Solvent: ClCCl
Product: Cc1nc(C#N)c(N)nc1-c1ccccc1

Procedure:
A reactor provided with a stirring device, a bromine feed and a calcium chloride tube is filled with 1.42 parts of 1,1-dicyano-3-methyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene in 20 parts by volume of dry methylene chloride. 0.34 parts by weight of ammonia in the form of a methanolic solution are added at -30°C. over a period of 4 days. After evaporation of the solvents in vacuo and recrystallisation of the crude product from methanol, 0.95 parts of 2-cyano-3-amino-5-phenyl-6-methyl-pyrazine are obtained in a field of 91% with respect to the starting azadiene.
Reaction SMILES: C(O[C:4]([CH:6]1[O:48][C:9]2[CH:10]=[C:11]3[C:16](=[C:17](C(OCC)=O)[C:8]=2[O:7]1)[CH2:15][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[S:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[CH2:13][CH2:12]3)=[O:5])C.[BH4-].[Li+].O.[O:52]1CCC[CH2:53]1>>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:29]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:14]2[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]4[O:48][C:6]([CH2:4][OH:5])([CH2:53][OH:52])[O:7][C:8]4=[CH:17][C:16]=3[CH2:15]2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c2c(cc3c1OC(C(=O)OCC)O3)CCN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: COc1ccc(C(CCCCCCN2CCc3cc4c(cc3C2)OC(CO)(CO)O4)Sc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.31 g of diethyl-6-[7-(3,4-dimethoxyphenyl)-7-[(4-methylphenyl)thio]heptyl]-5,6,7,8-tetrahydro-1,3-dioxolo [4,5-g]isoquinoline dicarboxylate and 0.045 g of lithium borohydride in 20 mL of tetrahydrofuran is stirred at room temperature for 3 hours, poured into water and the solvent evaporated in vacuo. The resulting mixture is extracted with methylene chloride. The methylene chloride extract is dried, filtered and the filtrate is evaporated in vacuo to yield a yellow oil. This oil is purified by flash chromatography using 2% methyl alcohol in methylene chloride to yield 0.1 g of the desired product as a white foam.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[S:19])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](I)[CH3:22].C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[NH:20])[S:19][CH2:21][CH3:22])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1ccc(CNC(=O)c2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSC(=N)Nc1ccc(CNC(=O)c2ccccc2)cc1
Yield: 88 %

Procedure:
To a mixture of N-benzoyl-4-thioureidobenzylamine (139.1 mg) and acetonitrile (10 ml), ethyl iodide (0.5 ml) was added and heated under reflux for 3 h. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1) to give 134.8 mg of the titled compound (yield, 88%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.BrC[CH2:21][CH2:22][Cl:23].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C.O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:21][CH2:22][Cl:23])=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: ClCCCBr
Reactant: COc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: ClCCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 76.2 %

Procedure:
The title compound was prepared from 3-chloro-2-(4-methoxy-phenyl)-2H-indazole (1.2 g, 4.9 mmol) and 1-bromo-3-chloropropane (3.1 g, 19.6 mmol), K2CO3 (2.8 g, 20.4 mmol), in methyl ethyl ketone (50 mL) was refluxed for 36 h. After the reaction mixture was diluted with water, the resulting aqueous mixture was extracted with ethyl acetate and sequentially washed with water, saturated aq. NaHCO3, water and brine. The combined organic portions were dried over Na2 SO4, filtered and concentrated in vacuo to afford the title compound (1.2 g, 80%). MS (APCI) m/z: 321 (M+1, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:19]1([C@@H:16]([NH:15][C:13]([C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:3]=2[CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[O:14])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](NC(=O)c1c(CN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(CNS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of 3-(aminomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (2e) (197 mg, 0.5 mmol) in DCM (30 ml) was added triethylamine (140 μL, 1.0 mmol) under N2. Upon cooling with ice-water bath, methanesulfonyl chloride (39 μL, 0.51 mmol) was added dropwise and the reaction mixture stirred at RT for additional 2 h. Washed the mixture with brine (10 mL) and the organic phase was separated and dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography eluting with 15-25% ethyl acetate/hexane to give the title compound (79 mg, 42%) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 1.95 (m, 2H), 2.99 (s, 3H), 4.88 (s, 2H), 5.25 (q, 1H), 6.66 (b, 2H), 7.30 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.20 (m, 2H). MS APCI, m/z=474 (M+1). LCMS: 2.16 min.
Reaction SMILES: [N:1]1([S:6]([CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C.O.CO>[N:1]1([S:6]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: NCCCS(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 32.6 %

Procedure:
A solution of Intermediate 27 (0.139 g) in isopropanol (7.6 ml) and water (1.3 ml) was treated with sodium borohydride (0.081 g), and the mixture was stirred at room temperature under nitrogen for 19 h. Glacial acetic acid (0.45 ml) was added cautiously and the mixture heated at 80° C. for 2 h. The solvents were evaporated in vacuo to give a white solid, which was dissolved in methanol and applied to a sulphonic acid ion exchange cartridge (10 g Isolute SCX). Elution with methanol followed by 10% 0.880 ammonia in methanol, and evaporation of the ammonia/methanol fraction gave the title compound as a white solid (0.027 g).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@H:10]([OH:12])[C@@H:9]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:32](Br)[C:33]#[C:34][CH3:35].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:32]([O:12][C@H:10]1[CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][C@@H:9]1[NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:33]#[C:34][CH3:35]
Reactant: CC#CCBr
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCO[C@H]1CN(C2CCCCC2)C[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a solution of compound of Example 1 (41 mg, 0.1 mmol) in THF (3 mL) cooled in an ice bath was added NaH (16 mg, 0.4 mmol) followed by 2-butynyl bromide (9.6 μL, 0.11 mmol). After being stirred in the ice bath for 3 hours, saturated NH4Cl was added followed by EtOAc. The EtOAc layer was separated, washed with brine, dried over MgSO4 and concentrated. Purification by reversed phase HPLC gave the title compound as a powder. MS calculated (M+H)+ 466, found 466.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[N:7]([CH2:10][CH2:11][OH:12])=[N+:8]=[N-:9].Br.O>C(Cl)Cl.C(N(CC)CC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:12][CH2:11][CH2:10][N:7]=[N+:8]=[N-:9])=[O:4]
Reactant: [N-]=[N+]=NCCO
Reactant: CC(Br)C(=O)Br
Agent: Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCCN=[N+]=[N-]

Procedure:
The synthesis was carried out in methylene chloride at 0° C. A solution of 2-bromopropionyl bromide in methylene chloride was added dropwise to a mixture of 2-azidoethanol in methylene chloride, triethylamine was added to neutralize the formed hydrobromic acid. After stirring at room temperature over-night water was added and the organic layer was extracted three times with water, the organic phase was then dried and the solvent evaporated. The product was a mixture of byproducts and had to be separated via silica gel column producing pure 2-azidoethyl 2-bromopropionate. Characterization was made with 1H-NMR and FT-IR.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COc1nc2c(Cl)ncnc2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nc2c(Cl)ncnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.4 %

Procedure:
To a 100 mL round bottomed flask was added 4-chloro-6-methoxypteridin-7(8H)-one (2.09 g, 9.8 mmol, 1.0 equiv) and anhydrous N,N-dimethylformamide (10 mL). Anhydrous potassium carbonate (6.8 g, 49 mmol, 5 equiv) was added in one portion to the reaction flask followed by the drop wise addition of iodomethane (2.09 g, 15 mmol, 1.5 equiv) over the course of 1 minute. The reaction was then vigorously stirred at room temperature. LC/MS analysis at 14 hours indicated the reaction was complete. The reaction mixture was then passed through a glass-sintered funnel and the recovered solids were washed with N,N-dimethylformamide (1×10 mL) and dichloromethane (3×15 mL) to give a dark brown filtrate. The solvent was evaporated at reduced pressure and the resulting powder was redissolved in dichloromethane (200 mL) and washed with saturated sodium chloride solution (200 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.72 g (pale brown powder, 77% yield) of 4-chloro-6-methoxy-8-methylpteridin-7(8H)-one as the desired material. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 4.04 (s, 3H), 3.56 (s, 3H). MS (EI) for C8H7ClN4O2: 227 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15]([C@@H:17]1[CH2:19][C@H:18]1[CH2:20][OH:21])#[CH:16].C(N(CC)CC)C>O1CCCC1.[Cu]I.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[OH:21][CH2:20][C@@H:18]1[CH2:19][C@H:17]1[C:15]#[C:16][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: C#C[C@@H]1C[C@H]1CO
Agent: [Cu]I
Agent: [Pd+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1
Yield: 93.9 %

Procedure:
To a stirring solution of 6-bromo-2-naphthoic acid (6.1, 1.0 g, 4.0 mmol), racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 0.5 g, 5.2 mmol), copper(I) iodide (30 mg, 0.16 mmol) and palladium(II) bis(triphenylphosphine)dichloride (56 mg, 0.08 mmol) in tetrahydrofuran (7.5 mL) under a nitrogen atmosphere was added triethylamine (2.5 mL) and the reaction was stirred for 1 week. The reaction was partitioned between 2N aqueous sodium hydroxide and ethyl acetate. The aqueous layer was acidified with conc HCl and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium chloride and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid (6.2, 1.0 g, 94%).