Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)c1
Temperature: 75 °C
Yield: 25.8 %

Procedure:
To a solution of 5-chloro-2-methyl-6-(3-methyl-benzyloxy)-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one from Example 4, Step E (25 mg, 0.06 mmol) in acetonitrile (2 mL) was added 2-hydroxy-2-methyl propionamidine HCl (13 mg, 0.09 mmol) and potassium carbonate (25 mg, 0.18 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (7.6 mg, 26% yield). MS (M+H): 491; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.40 (s, 3H), 5.47-5.56 (m, 2H), 7.17 (s, 1H), 7.26-7.31 (m, 3H), 7.54-7.58 (m, 2H), 7.92 (s, 1H), 8.14 (d, J=7.43 Hz, 1H), 8.76 (d, J=5.08 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:21])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1
Reactant: Oc1ccc(-c2ccc(F)cc2)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
2-Chloro-4′-fluorobiphenyl-4-ol (Preparation 73, 503 mg, 2.26 mmol) was dissolved in dichloromethane (5 mL) and acetic acid (5 mL). Concentrated sulfuric acid (0.05 mL) was added followed by N-iodosuccinimide (508 mg, 2.26 mmol) and the reaction stirred at room temperature for 2 hours before partitioning it between water and dichloromethane. The organic layer was separated and washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (553 mg, 70%) as an orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([OH:25])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24]>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:23]([OH:24])([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][OH:25])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCOCCOCCOCCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(O)(COCCOCCOCCO)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
p-Nitrobenzoyl chloride (390 g. 2.1 mole) and tetraethylene glycol (194 g, 1.0 mole) were dissolved in dry tetrahydrofuran (1 l) and the mixture evaporated under reduced pressure. The resulting thick oil was stirred under high vacuum (0.5 mm) overnight, during which time the mixture solidified. The mixture was slowly heated to 60° C. and maintained at this temperature for 5 hours. On cooling, the product was dissovled in ethyl acetate (2 l), saturated aqueous sodium bicarbonate (2 l) added and the mixture stirred at room temperature for 24 hours. The phases were separated, the organic phase washed with saturated sodium bicarbonate (3×), dried (MgSO4), filtered and the filtrate evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to give bis-(4-nitrobenzoyl)-tetraethylene glycol (406 g), m.p. 57.5°-58.5° C., which was homogeneous by TLC.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].CO.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[C:17]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCC3)c[nH]c2c1
Temperature: 75 °C

Procedure:
A 3 L three-necked flask equipped with a mechanical stirrer was charged with indole 6-carboxylic acid (220 g, 1.365 mole) and KOH pellets (764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MeOH (660 mL) were added and the mixture heated to 75° C. Cyclopentanone (603.7 mL, 6.825 mole, 5 equivalents) was added dropwise over 18 h using a pump. The reaction mixture was heated for an additional 3 h (after which the reaction was judged complete by HPLC) and cooled to 0° C. for 1 h. The precipitated potassium salt is collected by filtration, and washed with TBME (2×500 mL) to remove cyclopentanone self-condensation products. The brown solid was re-dissolved in water (2.5 L) and the solution washed with TBME (2×1 L). Following acidification to pH 3 with conc. HCl (425 mL), the beige precipitate was collected by filtration, washed with water (2×1 L) and dried under vacuum at 70° C. The crude product weighed 275.9 g (88.9% mass recovery) and had an homogeneity of 85% (HPLC).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>O1CCCC1.C(OCC)C>[CH3:11][C:9]1[S:8][C:7]2[C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1
Reactant: Cc1cc2cccc(Br)c2s1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2cccc(C(=O)O)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
The solution of 7-bromo-2-methylbenzo[b]thiophene (508) (0.908 g, 4.0 mmol) in tetrahydrofuran (16 mL) was cooled to −78° C. under nitrogen. n-butyllithium (2.40 mL, 6.0 mmol, 1.0M in Hexanes) was added dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 h, then poured on to the mixture of dry ice in ethyl ether (30 mL). The reaction was stirred to reach room temperature for 5 hours, followed by washing with 1N HCl, brine and dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained white solid was washed with hexanes to provide 2-methylbenzo[b]thiophene-7-carboxylic acid (509) (0.240 g, 31.2%). LC-MS ESI m/z: found 191.0 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].[CH2:8]([O:10][C:11](=[O:18])[C:12](=O)[CH2:13][C:14](=O)[CH3:15])[CH3:9].Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:5]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:4]=1)=[O:18])[CH3:9]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: N=C(N)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
2.241 g (20 mmol) of 2,2,2-trifluoro-acetamidine were dissolved in 80 ml ethanol and treated with 3.163 g (20 mmol) of 2,4-dioxo-pentanoic acid ethyl ester. The resulting solution was cooled to 0-5° C. and treated with 120 ml of HCl-saturated ethanol. The reaction mixture was allowed to warm-up to RT and stirred for additional 3 hours. The mixture was then added dropwise under cooling to 800 ml saturated NaHCO3 solution. The resulting mixture was then extracted twice with 300 ml DCM and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 3.1 g of a yellow oil. This residue was then purified by silicagel chromatography (eluent:heptane/ethyl acetate 100:0 to 30:70) leading to a colorless oil which crystallized spontaneously, leading to 1.3 g of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: COc1ccc(CNc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(C(=O)C2CCCc3ccccc32)c2ccc(OC)cc2)cc1
Yield: 83.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and [(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.97 g) as starting materials, N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.33 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.C(N(CC)CC)C.[C:39]([O:42][CH2:43][C:44](Cl)=[O:45])(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:42][CH2:43][C:44]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:12]=3)=[N:6][N:5]2[CH:31]=1)=[O:45])(=[O:41])[CH3:40]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Yield: 73.6 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.487 mmol), triethylamine (101 μL, 0.730 mmol), 2-chloro-2-oxoethyl acetate (63 μL, 0.584 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 385, the title compound (183 mg, 74%) was obtained as a gray powder.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O>N1C=CC=CC=1>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-methyl-4-nitro-1-pentanol (7 gm) in pyridine (40 ml) was cooled in an ice bath and treated with tosyl chloride (19 gm) added in portions over 20 mins. When the addition was complete the mixture was stirred at room temperature for 1 hr. Water (20 ml) was then added and the mixture stirred for 15 mins. The mixture was poured into water and extracted twice with ethyl acetate. The ethyl acetate solution was washed successively with water, citric acid solution, water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The product was obtained by crystallisation from ether: 60/80 petroleum ether. Yield 8.18 gm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].Br[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:33]1[CH:34]=[C:29]([C:16]#[C:15][CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cc(F)cc(F)c3)CC2)n1
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a suspension of Compound 274c (70 mg, 0.27 mmol), sodium acetate trihydrate (74.2 mg, 0.55 mmol) and 1-bromo-3,5-difluorobenzene (33.5 μl, 0.27 mmol) in 2.05 mL of DMF flushed with nitrogen was added tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.014 mmol) and the reaction mixture was put into a microwave oven (Biotage) at 120° C. for 10 min. Dilution with EtOAc, washing with H2O and drying over Na2SO4 followed by evaporation and purification of the residue by automated flash liquid chromatography (Horizon™-Biotage) (PE-CH2Cl2 6:4) afforded 74 mg (73.7%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnn2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Fluorobenzonitrile (0.847 g, 7 mmol), 1H-[1,2,3]triazole (0.483 g, 7 mmol), Cs2CO3 (2.27 g, 7 mmol) and DMF (8 ml) and a magnetic stirrer were placed in a vial. The mixture was heated with stirring for 3 h at 80° C. Extractive work-up (EtOAc/H2O) and subsequent drying (Na2SO4) gave a crude product which was purified on silica giving 0.55 g (46%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[O:25]1[CH2:30][CH2:29][O:28][C:27]2[C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=[CH:34][C:26]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:35]([C:31]2[C:27]3[O:28][CH2:29][CH2:30][O:25][C:26]=3[CH:34]=[CH:33][CH:32]=2)=[O:36])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3cccc4c3OCCO4)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid (36%). MS 494 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-])=O.O.Cl>C(O)(C)C>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C(C)n1ncc2ccc(N)cc21

Procedure:
Ethyl 2-(6-nitroindazol-1-yl)propionate (1 g), water (3.7cm3) and reduced iron (2.3 g) were stirred in isopropanol (17cm3) at room temperature. Concentrated hydrochloric acid (0.14cm3) was added and the mixture stirred and heated under reflux for 20 minutes. The mixture was filtered through hyflo whilst hot and filter pad washed with ethanol. The combined filtrate was concentrated under vacuum and the residue purified by chromatography (SiO2 ; CHCl3 : ether, 3:1) to give ethyl 2-(6 aminoindazol-1-yl)propionate (0.649). M+ =233
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:31])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[CH3:31]
Reactant: O=C(O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCOC3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (Example 101.0 and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=427.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[C:16]([S@:20]([NH2:22])=[O:21])([CH3:19])([CH3:18])[CH3:17]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:17][C:16]([S@:20](/[N:22]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:9][CH:10]=1)=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Oc2cncnc2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Oc2cncnc2)cc1
Temperature: 55 °C
Yield: 82.8 %

Procedure:
A mixture of 4-(pyrimidin-5-yloxy)benzaldehyde (666 mg, 3.33 mmol), (R)-(+)-tert-butanesulfinamide (450 mg, 3.71 mmol) and copper sulfate (796 mg, 4.99 mmol) in anhydrous in dichloroethane (7.648 mL) and under argon was heated at 55° C. for ˜21 hours. The reaction mixture was allowed to cool to room temperature. The slurry was filtered through a celite pad, eluted with DCM (5×10 mL). The combined filtrates were concentrated under reduced pressure and the resulting yellowish oil was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing (R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide (836 mg) as a pale viscous oil. LCMS m/z 304.0 (M+H)+, Rt 0.79 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[S:17][C:18]([CH2:21]Br)=[CH:19][N:20]=1>>[Br:15][C:16]1[S:17][C:18]([CH2:21][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:19][N:20]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCc1cnc(Br)s1
Product: N#Cc1ccc(N(Cc2cnc(Br)s2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-(4-cyanophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(bromomethyl)thiazole
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:15]1([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=2[C:32]2[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:33]=2[C:41]#[C:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCOCC1>O>[C:43]1([C:42]#[C:41][C:33]2[CH:34]=[CH:35][C:36]([NH2:38])=[CH:37][C:32]=2[C:24]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:23]=2[C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=[N+]([O-])c1ccc(C#Cc2ccccc2)c(-c2cc([N+](=O)[O-])ccc2C#Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(C#Cc2ccccc2)c(-c2cc(N)ccc2C#Cc2ccccc2)c1
Yield: 46 %

Procedure:
A solution of sodium dithionite (8.00, 0.0460 mole) and sodium carbonate (7.01 g, 0.0661 mole) in water (50 ml) was stirred under a nitrogen atmosphere while 2,2'-bis(phenylethynyl)-5,5'-dinitrobiphenyl (0.500 g, 0.00112 mole) was added followed by dioxane (50 ml). The reaction mixture was stirred and refluxed for 2 hours and then the solvent was removed under vacuum. The residue was extracted with benzene and the filtered benzene extracts were freeze-dried to afford 0.198 g (46%) of 2,2'-bis(phenylethynyl)-5,5'-diaminobiphenyl, m.p. 159°-161° C. after recrystallization from chloroform-cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[CH3:15][Mg]Br.Cl>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2c(Cl)cccc2nc1Cl
Temperature: 0 °C

Procedure:
Dissolved 2,5-dichloroquinoline-3-carbaldehyde (2.46 g, 11 mmol) in THF (70 mL) and submerged in an ice-bath. Added methylmagnesium bromide (5.4 mL, 16 mmol) and removed the ice-bath. After 10 min. the reaction mixture was poured into 1.0 N HCl and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was chromatographed on 80 g silica gel column with 0-40% EtOAc:Hex. The desired fractions were combined and concentrated to yield an off white, crystalline solid. 1H NMR (400 MHz, DCM-d2) δ ppm 1.60 (d, J=6.26 Hz, 3 H) 2.35 (br. s., 1 H) 5.36 (q, J=6.39 Hz, 1 H) 7.61-7.67 (m, 2 H) 7.87-7.94 (m, 1 H) 8.75 (s, 1 H). LC-MS (+esi, M+H+=242.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru].O>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 2 liter Parr autoclave was charged with 50 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 650 grams of dionized water, and 25 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 80° C. with stirring at approximately 1000 rpm (revolutions per minute) and held for 6 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that complete conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 100% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 2.06:1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccnc2n1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of {(S)-1-[3-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester (35 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL) and the mixture was stirred at RT for 3 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[3-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethylamine as an orange oil (23 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13](O)=[O:14])[C:5]2=[O:16].S(Cl)([Cl:19])=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]([Cl:19])=[O:14])[C:5]2=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2cc(O)c(O)cc2c1=O
Product: O=C(Cl)c1coc2cc(O)c(O)cc2c1=O

Procedure:
6,7-Dihydroxychromon-3-carboxylic acid (888 mg) together with thionyl chloride (25 ml) were refluxed for one hour. Any unreacted thionyl chloride was then removed from the reaction mixture by distillation. Benzene was added to the residue, and the mixture was subjected to distillation. The residue was triturated with dichloromethane to obtain the desired product (719 mg).