Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH2:39]/[C:40](=[N:43]/[H])/[NH:41][OH:42])[CH:35]=[CH:36][C:37]=1[Cl:38]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:42][N:41]=[C:40]([CH2:39][C:34]4[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=4)[N:43]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: [H]/N=C(/Cc1ccc(Cl)c(Cl)c1)NO
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)c(Cl)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 66.1 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (46 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (66 mg, 66%).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CCNCC
Agent: [N-]=C=S
Solvent: CCCCC
Product: CCN(CC)C(=S)NC1(N=NC(C)(C)C)CCCCC1

Procedure:
To 9.12 grams (.0395 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 10° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.89 grams (.0395 moles) of diethylamine. The reaction mixture was stirred for 3 hours at room temperature, adding pentane periodically to keep the viscosity low. The pentane was stripped from the reaction mixture to leave a yellow viscous oil weighing 11.4 grams (95% crude yield). The infrared spectrum of the product had a strong broad band at 1520 cm-1 and a sharp NH band at 3300 cm-1 and the isothiocyanate band at 2040 cm-1 was very weak indicating there was a trace of the starting material still present.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH2:20])[C:12]#[CH:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCOCCOCCN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: C#CCOCCOCCNc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 15.6 %

Procedure:
To 1-chloro-4-nitrobenzene (152 mg, 0.97 mmol, 1.0 equiv.) was added neat 2-(2-(prop-2-ynyloxy)ethoxy)ethanamine (s-5) (900 mg, 6.31 mmol, 6.5 equiv.), and the resulting slurry was heated to 100° C. for 19 hours. At the end of this period, the heating bath was removed, and the reaction content was mixed with water (50 mL) and then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% EtOAc in CH2Cl2, then 30% EtOAc in CH2Cl2 to yield 4-nitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-7) as a dark yellow oil (40 mg, 16%). IR (thin film) 3351 (m), 3239 (m), 2858 (w), 2112 (w), 1599 (s), 1535 (w), 1500 (w), 1467 (s), 1284 (s), 1086 (s), 1034 (w); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=9.2 Hz, 2H), 6.53 (d, J=9.2 Hz, 2H), 5.05 (bs, 1H), 4.19 (d, J=2.4 Hz, 2H), 3.76-3.70 (m, 2H), 3.70-3.64 (m, 4H), 3.38 (q, J=5.3 Hz, 2H), 2.45 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) □ 153.4, 138.0, 126.4, 111.2, 79.5, 74.9, 70.3, 69.1, 69.0, 58.5, 42.9. HRMS (ES+) calc'd for C13H16N2O4 (M+H) m/z 265.1144 Found 265.1177.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:12](=[O:13])[C:7]2=[C:6]([O:22]CC2C=CC=CC=2)[C:5]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:3])[CH3:2]>[OH-].[OH-].[Pd+2].C(O)C>[C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:12](=[O:13])[C:7]2=[C:6]([OH:22])[C:5]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2n(c1C(C)=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 6-acetyl-8-(benzyloxy)-2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (140 mg, 0.30 mmol) and Pearlman's catalyst (5.0 mg, 20% Pd(OH)2 on carbon) in ethanol (20 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature overnight. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to provide the titled product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)ccn1
Yield: 41.2 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (150 mg, 0.46 mmol) in 1,2-dimethoxyethane (4 mL) was added 2-methoxypyridin-4-ylboronic acid (84 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol), and 2 M Na2CO3 (680 μL, 1.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with (0-20% ethyl acetate/hexanes) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (76 mg, 42%). ESI-MS m/z calc. 401.2. found 402.3 (M+1)+. Retention time 1.88 minutes.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH2:22][C@@H:21]([C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][NH:8][CH2:9]1)[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 83 %

Procedure:
To a solution of 2-[(R)-1-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-pyridine 570 mg (0.96 mmol) dissolved in toluene (4 mL) was added 0.31 mL (2.89 mmol) of 1-chloroethyl chloroformate and 0.491 mL (2.89 mmol) of Hunig base subsequently, and the mixture was heated at 100° C. for 40 minutes, then concentrated in vaccuo. The residue was dissolved in methanol (5 mL) and stirred at room temperature over night. The mixture was concentrated in vaccuo and diluted with ethyl acetate, then washed with aq. sodium bicarbonate solution twice. The separated organic layer was dried over sodium sulfate and concentrated in vaccuo after filtration yielded 0.40 g (83%) of the title compound as a light brown oil. ES-MS m/e: 501.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[N:10]=[C:11]([NH2:13])[S:12][CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of 90% ethyl bromopyruvate (54.2 g, 0.25 mol) and thiourea (20 g, 0.263 mol) in 500 mL absolute ethanol was heated at reflux for 1 h and then stirred at ambient temperature for 2 h. Ethanol was removed in vacuo and the residue was suspended in ice-water and neutralized with solid potassium carbonate until basic. The solid was filtered, washed thoroughly with water and air-dried to give 42 g of ethyl-2-amino-4-thiazolecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[N:5](C)[C:6](=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[NH:5][CH3:6]
Reactant: CN(C(=O)c1ccccc1)c1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of 3',5'-dichloro-N-methylbenzanilide (2.317 g) in tetrahydrofuran was added lithium aluminum hydride (380 mg) in an ice-bath and the resulting suspension was stirred at the same temperature for one hour. The reaction mixture was quenched with saturated ammonium chloride and filtered through celite pad. The inorganic material on the celite was washed with ethyl acetate. Methanol was added to the filtrate and stirred at ambient temperature for half an hour. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:9, V/V) to afford 3,5-dichloro-N-methylaniline (1.38 g) as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](=[O:12])(O)[O-].[Na+].II.[I-].[K+]>O.C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][S:1][C:2]2[CH:7]=[CH:6][C:9]([OH:12])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1
Reactant: O=C([O-])O
Reactant: Oc1ccc(S)cc1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Oc1ccc(SSc2ccc(O)cc2)cc1
Yield: 97.5 %

Procedure:
A solution of 4-mercaptophenol (200 g., 1.6 m.) in 300 ml. 60% aqueous ethanol was brought to pH 7 by the addition of sodium bicarbonate. A solution of iodine (200 g., 0.8 m.) and potassium iodide (50 g.) in 300 ml. water was added until a yellow end point was reached. The product was filtered off, washed with water and dried. Yield: 97.5%, mp. 144°-6° (lit. 148°-50°). The 1H nmr was consistent with the disulfide structure of the formula: ##STR2##
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:12]1([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CN2CCCCC2)n1
Reaction time: 0.75 h
Yield: 103.5 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (5.8 ml) was added piperidine (0.428 ml, 4.33 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 30 mins when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred for 45 mins. The mixture was loaded onto an aminopropyl cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane and methanol, and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in ethyl acetate (25 ml) and washed with sodium hydroxide solution (2M, 3×25 ml). The aqueous layer was acidified to pH6 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (376 mg).
Reaction SMILES: O[C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: COc1cc2c3c(c1)c(O)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c3c(c1)c(Cl)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydro-7-hydroxy-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (3 g) and phosphorus oxychloride (2.2 ml) was stirred at 80° C. for 1 hour. The mixture was poured into ice-water and the precipitates were collected and washed with water to give yellow crystals of 2,3-dihydro-7-chloro-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH:23]([C:26]1[C:30]([C:31]([O:33]CC)=[O:32])=[CH:29][NH:28][N:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:23]([C:26]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]([CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)[N:27]=1)([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1c[nH]nc1C(C)C
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(C(C)C)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (7.13 g), ethyl 3-isopropyl-1H-pyrazol-4-carboxylate (6.17 g), potassium carbonate (4.72 g) and N,N-dimethylformamide (70 ml) was stirred at 80° C. overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (4.83 g) and ethanol (150 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the mixture, then the mixture was acidified with dilute hydrochloric acid. The crystals obtained were collected by filtration to yield 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (11.39 g, yield: 78%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 194–195° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4([C:32]#[N:33])[CH2:31][CH2:30]4)[CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4([C:32]#[N:33])[CH2:31][CH2:30]4)[CH:24]=3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[N:10]=2
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Potassium thiocyanate (4.44 g, 45.7 mmol) was suspended in acetic acid (100 mL), and the mixture was stirred at room temperature for 30 min. A solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (4.1 g) in acetic acid (100 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 30 min. A solution of bromine (2.65 g, 16.6 mmol) in acetic acid (100 mL) was added dropwise to the obtained solution for 30 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 16 hr. The yielded yellow solid was filtered off, and washed with acetic acid, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.68 g, total of 2 steps 59%) as a yellow amorphous substance.
Reaction SMILES: [CH2:1]([N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO.[BH4-].[Na+]>C(O)(=O)C>[CH2:1]([N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCn1c(=O)c2c(ncn2CCCCC(C)O)n(C)c1=O

Procedure:
25 g of 1-n-hexyl-3-methyl-7-(5-oxohexyl)-xanthine, 100 ml of methanol and 1.0 g sodium borohydride are stirred at ambient temperature for 30 minutes. The mixture is then acidified with crystalline acetic acid to a pH-value of 5. The alcohol is evaporated and the residue is dissolved in 200 ml of methylene chloride and washed with 2N sodium hydroxide solution and with water. After evaporation of the methylene chloride, the product is recrystallised from 250 ml of diisopropyl ether. The 1-n-hexyl-3-methyl-7-(5-hydroxyhexyl)-xanthine obtained (88% of theory) has a melting point of 68° to 69° C.
Reaction SMILES: CS([C:5](=[CH:9][CH2:10][O:11][CH3:12])[CH2:6][O:7][CH3:8])(=O)=O.[CH2:13]([C:20]1[O:21][CH:22]=[C:23]([CH3:25])[N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:25][C:23]1[C:22]([OH:21])=[C:5]([CH2:6][O:7][CH3:8])[C:9]([CH2:10][O:11][CH3:12])=[C:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:24]=1
Reactant: Cc1coc(Cc2ccccc2)n1
Reactant: COCC=C(COC)S(C)(=O)=O
Product: COCc1c(Cc2ccccc2)nc(C)c(O)c1COC
Temperature: 190 °C

Procedure:
A mixture of 19.4 g (0.1 mole) of 2-methylsulfonyl-1,4-dimethoxy-but-2-ene and 34.6 g (0.2 mole) of 2-benzyl-4-methyloxazole is heated for 10 hours at 190° C. After it has cooled, unconverted oxazole and sulfone are distilled off in a high vacuum. The residue is chromatographed over silica gel (using ethyl acetate and methanol). 5.5 g of 2-methyl-4,5-di-(methoxymethyl)-6-benzyl-pyridin-3-ol, identified by the NMR spectrum, are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.CI>CO>[CH3:1][N:2]([CH3:21])[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:31]([NH:30][C:24]4[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=4[F:29])=[N:20][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Fc1cccc(F)c1N=C=S
Reactant: CNc1ccc(Oc2ccnc(C(=O)N(C)C)c2)cc1N
Solvent: CO
Solvent: CI
Product: CN(C)C(=O)c1cc(Oc2ccc3c(c2)nc(Nc2c(F)cccc2F)n3C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid dimethylamide (1 eq) in methanol was treated with 2,6-difluorophenylisothiocyanate (1 eq) and stirred overnight. To the reaction mixture, methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS: MH+=424.1
Reaction SMILES: Br[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:13][C:14]1[C:15]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:17]=[CH:18][CH:19]=1>C1(C)C=CC=CC=1.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>[CH3:13][C:14]1[C:15]([C:2]2[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reactant: COC(=O)c1nc(C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C)ccc1-c1ncccc1C
Temperature: 150 °C
Yield: 18.9 %

Procedure:
To the title compound of step B (509 mg, 2.2 mmol) and the title compound of step C (1.1 g, 2.9 mmol) in PhCH3 (6.6 mL) was added Pd(PPh3)4 (225 mg, 0.2 mmol). The reaction was degassed with N2 and heated at 150° C. for 1.5 h using microwave reactor. The reaction was cooled to rt, diluted with H2O and extracted with EtOAc. The organic layer was dried (MgSO4). Purification via silica gel chromatography (0-100% EtOAc in heptane) gave the title compound (101 mg, 18%). MS (ESI) mass calcd. for C14H14N2O2, 242.3; m/z found 243 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:49][CH2:48]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:48][CH2:49]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1

Procedure:
The title compound was prepared [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (391 mg, 82%).