Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.[BH3-][C:55]#N.[Na+]>C=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([CH3:55])[CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (150 mg, 0.21 mmol, 1.00 equiv) in HCHO (in water) (6 mL), NaBH3CN (15 mg, 1.10 equiv), and acetic acid (5 drops). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 5 mL of sodium bicarbonate, extracted with 2×5 mL of dichloromethane, and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 1×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 13.3 mg (9%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.96 (d, J=5.1 Hz, 1H), 8.76 (d, J=9.3 Hz, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 8.05 (s, 2H), 7.89˜7.87 (m, 1H), 7.71˜7.62 (m, 5H), 7.59˜7.56 (m, 2H), 4.72 (s, 2H), 3.79 (s, 2H), 3.66 (d, J=5.1 Hz, 4H), 3.50˜3.34 (m, 2H), 3.15˜3.04 (m, 6H), 2.89˜2.85 (m, 6H), 2.80˜2.60 (m, 2H), 2.04 (d, J=4.5 Hz, 4H), 1.83 (d, J=5.4 Hz, 2H). MS (ES, m/z): 742 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:40](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:40][NH:5]2
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a solution of 3-bromo-2-methyl aniline (0104) (0.50 g, 2.69 mmol) in chloroform (5 mL) was added potassium acetate (0.28 g, 2.82 mmol). The mixture was cooled with ice-water bath and then acetic anhydride (0.50 mL, 5.37 mmol) was added to it. Ice-water bath was then removed and the resulting mixture was stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.14 g, 0.54 mmol) was then added followed by isoamyl nitrite (0.80 mL, 5.90 mmol). The mixture was then heated under reflux for 18 hours. The reaction mixture was allowed to cool, and was partitioned between chloroform (3×10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography (ethyl acetate in petroleum ether, 10% v/v) to give 1-(4-bromoindrazol-1-yl)-ethanone (0105) as an orange solid (0.31 g, 49%), and 4-bromo-1H-indazole (0106-3) as a pale orange solid (0.21 g, 40%). Compound 0105: LCMS: 239 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 2.80 (s, 3H), 7.41 (t, J=6.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 8.15 (s, 1H), 8.40 (d, J=6.8 Hz, 1H). Compound 0106: LCMS: 197 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 7.25 (t, J=6.0 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 8.12 (s, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=O)=O.[Br-:14].[Li+]>CC(C)=O>[Br:14][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCCC1CCOCC1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: BrCCC1CCOCC1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To 2-(tetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (5.4 g) in dry acetone at room temperature was added lithium bromide (9 g) in one go. The reaction was heated to reflux for 4 hours, under nitrogen. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried by passing through a hydrophobic frit, and concentrated in vacuo. The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a colourless oil (3.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:3]=1.[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]>C(OCC)(=O)C>[CH:9]([O:8][C:6]1[N:7]=[C:2]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:5]=1)([CH3:11])[CH3:10]
Reactant: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(Oc3ccccc3C(F)(F)F)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 99 %

Procedure:
This compound was prepared from (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-hydroxy benzotrifluoride in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 99% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC.CCCCCC.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:10]([OH:15])[OH:11])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
3-Bromobenzonitrile (3.6 g, 20 mmol) in anhydrous THF (100 ml) is treated with triisopropyl borate (13 ml, 56 mmol) followed by 1.6 M butyllithium in hexane (14 ml, 22 mmol) over 15 min. at −78° C. The reaction is stirred at −78° C. for 45 min . then warmed to room temperature over 60 min. The reaction mixture is poured into 40 ml 2 N HCl and the precipitated solid is collected . The filter cake is washed with water (3×) and methylene chloride (3×) to yield 3-cyanophenyl boronic acid (2.3 g, 15.6 mmol). 1H NMR (CDCl3, 300 MHz) δ 8.4 (br, 2H), 8.13 (s, 1H), 8.07 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H). EI MS M+ 147.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([O:10][CH3:11])=[O:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:29]1([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:29]1([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([O:10][CH3:11])=[O:9])=[O:42])=[O:38])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H]1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H]1CCCCN1C(=O)CNC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of methyl (2R)-2-piperidinecarboxylate hydrochloride (1.0 g, 5.56 mmol) and HOBt (0.90 g, 6.67 mmol) in CH2Cl2 (20 mL) was added 4-methylmorpholine (2.44 mL, 22.24 mmol), N-{[(phenylmethyl)oxy]carbonyl}glycine (1.16 g, 5.56 mmol), and EDCI (1.28 g, 6.67 mmol). After stirring overnight, the solution was washed 6 N aq. HCl (100 mL) and water (100 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), and then dried over anhydrous MgSO4 and concentrated in vacuo to provide methyl (2R)-1-(N-{[(phenylmethyl)oxy]carbonyl}glycyl)-2-piperidinecarboxylate (2.029 g, 99%). LCMS: (M+H)+: 335.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3c(ncn3C)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cnc2c1ccn1c(=O)c(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c21
Yield: 92.3 %

Procedure:
2.44 g (5.5 mmol) of methyl 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylate in 50 ml of ethanol were treated with a solution of 1.4 g (21 mmol) of potassium hydroxide (content 86%) in 50 ml of water. After boiling under reflux for 4 hours 200 ml of water were added and the mixture was adjusted to pH 1-2 with 2N hydrochloric acid while cooling with ice. The precipitate obtained was filtered off, washed with water and dried. There were obtained 2.16 g (92%) of 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylic acid as yellow crystals with m.p. 227-229° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2].[OH-:17].[Na+]>>[C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:17])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1c(I)cc(I)c(OCC(=O)O)c1I
Agent: [Na+]
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I

Procedure:
27.3 g (49 mmol) of 3-cyano-2,4,6-triiodophenoxyacetic acid is stirred in 100 ml of 2 N sodium hydroxide solution for 3 hours at 50° C. The resultant alkaline solution is filtered over active carbon for purifying and decolorizing and then brought to pH 2 by adding 2 N hydrochloric acid. After several hours of stirring in an ice bath, the yield is 23.9 g (85% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)nc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(Cl)cc2)nc1
Yield: 94.2 %

Procedure:
4-Chlorophenoxy-5-nitropyridine (19.9 g) and platinum dioxide (0.1 g) were suspended in a mixture of tetrahydrofuran (100 ml) and ethyl acetate (50 ml), and catalytic reduction was carried out until 5.0 liters of hydrogen were absorbed. After removal of the catalyst by filtration, the solvent was distilled out under reduced pressure. The precipitated crystals were washed with a small amount of ether to give 16.5 g of 4-chlorophenoxy-5-aminopyridine as white crystals. M.P., 87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:7][C:6]=2[CH:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].P(OCC)(OCC)[O:37]CC>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([OH:37])([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:25]=1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (15 g, 41.7 mmole) in 780 ml of tetrahydrofuran was cooled to -78° C. and 147 ml (167 mmole in tetrahydrofuran) of potassium hexamethyldisilazide solution was added. After stirring for 1 hour, 28.7 ml of triethyl phosphite (166.7 mmole) was added and anhydrous oxygen gas was rapidly bubbled through the resulting solution. The reaction temperature was then raised to 0° C. and allowed to stir for an additional hour. Oxygenation was then discontinued and the reaction was quenched by the addition of 50 ml of acetic acid. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate, and brine and then dried over anhydrous sodium sulfate. Concentration of the dried organic solution afforded a solid which, upon trituration in hexane, gave 14.8 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[O:3]1.C([Mg]Cl)(C)C.[F:18][C:19]([F:38])([F:37])[C:20]1[O:24][C:23]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:12][C:2]1([F:1])[O:3][C:4]2[CH:10]=[C:9]([OH:11])[C:8]([C:28]3([OH:35])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]([CH2:25][C:23]4[O:24][C:20]([C:19]([F:38])([F:37])[F:18])=[CH:21][CH:22]=4)[C:27]3=[O:36])=[CH:7][C:5]=2[O:6]1
Reactant: Oc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2,2-difluoro-1,3-benzodioxol-5-ol (Jacobus et al., WO 2004/4048320) (1.15 g, 6.60 mmol) in anhydrous tetrahydrofuran at 0° C. was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 3.3 mL, 6.6 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (1.95 g, 6.60 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 96 h. A saturated aqueous solution of ammonium chloride (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluted with a 0% to 35% gradient of ethyl acetate in hexanes afforded 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (2.54 g, 73%) as a pale orange solid: MS (ES+) 451.3 (M−17).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][C:19]1[O:23][C:22]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)O)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:15]([CH:24]([C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[N+:16]=[N-:17]
Reactant: Cc1ccc(C(O)C2CCOCC2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(N=[N+]=[N-])C2CCOCC2)o1
Temperature: 0 °C
Reaction time: 22 h
Yield: 69.8 %

Procedure:
6.08 g (22 mmol, 1.1 eq) of diphenylphosphoryl azide were added dropwise to a solution of 4.43 g (20 mmol, 1 eq) of (5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methanol at 89% in 60 ml of toluene. The reaction medium was cooled to 0° C. and then 3.3 ml (22 mmol, 1.1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 22 hours. The reaction medium was separated by settling out and the organic phase was washed with water and then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column Analogix SF40-240 g, Spot II) eluted with heptane/ethyl acetate (95/5). 3.09 g of 4-[azido-(5-methylfuran-2-yl)methyl]tetrahydropyran were obtained. Yield=70%.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:15][CH2:13][CH3:14]
Reactant: CCS
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of 2-chloro-2′,4′-difluoroacetophenone (10 g, 0.053 mol) and ethyl mercaptan (3.6 g, 0.058 mol) in methanol (200 ml), potassium carbonate (8.8 g, 0.064 mol) was added under ice cooling, followed by stirring at room temperature for 1.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ether. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting oil was distilled under reduced pressure (bp: 115 to 118° C., 2 mmHg), whereby 2′,4′-difluoro-2-(ethylthio)acetophenone (11.4 g, yield: 99.9%) was obtained as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:26])=[N:23][CH:24]=2)[CH:21]=1)=O)(C)(C)C>ClCCl>[CH3:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:26])=[N:23][CH:24]=2)[CH:21]=1
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccc(N(C)C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc2cnc(C(=O)c3ccc([N+](=O)[O-])c(C(=O)OC)c3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1.3 ml of trifluoroacetic acid are added to 460 mg (1.01 mmol) of methyl 5-({6-[(tert-butoxycarbonyl)(methyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoate in 5 ml of dichloromethane and the mixture is stirred at ambient temperature overnight. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and basified with a saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. 350 mg of a red powder are obtained. Melting point: 183° C.; 1H NMR (d6-DMSO): 2.79 (3H, d), 3.90 (3H, s), 7.11 (1H, d), 7.77 (1H, s), 7.82 (1H, d), 8.31 (1H, d), 8.66 (1H, d), 8.75 (1H, s), 9.01 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9](=[O:10])[CH2:11][CH:20]([OH:21])[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=O
Reactant: CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCOC(=O)C(O)CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 23.6 %

Procedure:
A mixture of 1,1-bis(4-fluorophenyl)acetone (2.4 g) and ethyl glyoxylate (47% solution in toluene, 2.1 g) was stirred at 130° C. for 3 days. The reaction mixture was cooled to ambient temperature. The mixture was purified by silica gel column chromatography (n-hexane:EtOAc=4:1) to give ethyl 5,5-bis(4-fluorophenyl)-2-hydroxy-4-oxopentanoate (800 mg) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:3]2[C:2]([NH:1][C:29]([O:31][CH3:32])=[O:30])=[CH:11][CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methylamino]benzoate (10 g) in pyridine (50 ml) was added dropwise methyl chloroformate (9.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to afford pale yellow needles (10.5 g, 90%), m.p. 113°-115° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[C:8]([Cl:14])=[N:9][C:10](Cl)=[N:11][CH:12]=1>C1COCC1.N1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:10]1[N:11]=[C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:7]=[C:8]([Cl:14])[N:9]=1)[CH3:2]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCNCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(CC)c1cc(Cl)nc(N(CC)CC)n1

Procedure:
Diethylamine (80 g) is reacted with trichloropyrimidine (50 g) in THF. The reaction after chromatography yields a mixture of the mono- and di-adduct. This material is dissolved in pyridine (58 g) and reacted with diethylamine (35 g) at 50° for 3 h. The reaction is concentrated to a residue. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is separated and concentrated. The residue is chromatographed on silica gel, eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give 2,4-bis[diethylamino]-6-chloropyrimidine. This material is dissolved in pyridine (100 g) and reacted with piperazine (40 g) at 100° for 50 h. Following the above workup procedure the title compound is obtained, NMR (CDCl3) 1.15, 2.90, 3.45 and 4.9 δ.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][C:32]#[CH:33]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:34]1([CH2:30][CH2:31][C:32]#[C:33][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Clc1nc2ccccc2o1
Reactant: C#CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1nc2ccccc2o1)CCc1ccccc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 40.5 %

Procedure:
To a solution of CuI (15 mg, 81 mmol) in triethylamine (3 mL) were added 2-chlorobenzo[d]oxazole (250 mg, 1.63 mmol), (PPh3)2PdCl2 (57 mg, 81 μmol), triphenylphosphine polymer bound 3 mmol/g (98 mg, 293 μmol) and a solution of 1-(but-3-ynyl)benzene (250 mg, 1.92 mmol) in DMF (0.5 mL). The reaction mixture was stirred for 25 min. at 120° C. in the microwave cavity. The reaction was quenched as described in Example 1. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 163 mg (0.66 mmol, 40%) of 2-(4-phenylbut-1-ynyl)benzo[d]oxazole as an orange oil.