Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[CH:27]=3)=[O:25])[CH:18]=2)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:15]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:33])[CH3:34])[CH:27]=4)=[O:25])[CH:18]=3)[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: COC(=O)c1cc(N)ccc1Oc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
Potassium thiocyanate (1.02 g, 10.5 mmol) was suspended in acetic acid (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of methyl 5-amino-2-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]benzoate (1.13 g, 2.62 mmol) in acetic acid (10 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (460 mg, 2.88 mmol) in acetic acid (5 ml) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 3 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was is concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (1.15 g, 90%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1Cl
Yield: 70.5 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (274 mg, 70%). MS (ISP) 375.3 [(M+H)+]; mp 193° C.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1>>[CH3:42][C:38]1([CH3:43])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]2[CH:33]=[C:32](/[C:26](/[Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25]/[C:22]3[S:21][C:20]([CH2:19][OH:18])=[CH:24][CH:23]=3)[CH:41]=[CH:40][C:39]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(/C(=C/c3ccc(CO)s3)[Si](C)(C)C)ccc21

Procedure:
Following General Procedure A, 5-[(trimethylsilyl)ethynyl]thiophen-2-ylmethyl tert-butyldiphenylsilyl ether (Compound 13, 0.75 g, 1.8 mmol) and 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (0.46 g, 1.62 mmol) were coupled to give the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][CH2:16]Cl>C1COCC1>[CH3:14][O:15][CH2:16][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: COCCl
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(N)c([N+](=O)[O-])c1
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (60%, 2.70 g (67.5 mmol)) in THF (100.0 ml), under cooling with ice and with stirring, 4-amino-3-nitrophenol (10.0 g (64.9 mmol)) was added. To the resulting mixture, after 10 minutes' stirring under cooling with ice, chloromethyl methyl ether (5.50 g (68.3 mmol)) was added dropwise and the mixture was stirred at 5° C. for one hour and at room temperature for one hour, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated aqueous solution of sodium bicarbonate successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Then the residue was subjected to silica gel column chromatography with chloroform-ethanol (100:1) as eluent to give 7.69 g (60%) of 4-methoxymethoxy-2-nitroaniline as red oil.
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ8.50 (1H, d, J=5.5 Hz), 7.89 (1H, d, J=8.7 Hz), 7.82 (1H, s), 7.40 (1H, s), 7.06 (1H, d, J=6.6 Hz), 6.72 (1H, d, J=5.5 Hz), 4.74-4.65 (2H, m), 4.31-3.68 (5H, m), 3.60-3.55 (2H, m), 2.68 (3H, s), 2.54-2.46 (2H, m), 1.95-1.87 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 478, found 478.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O=P(Cl)(Cl)Cl.O.CN([CH:26]=[O:27])C>>[CH:26]([C:5]1[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2](=[O:1])[N:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2)=[O:27]
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (1 g, 4.0 mmol) was dissolved in 2 ml DMF followed by the addition of POCl3 (1.0 ml, 11 mmol). The reaction mixture was stirred for 1 h, poured into 100 ml water and extracted three times with 100 ml dichloromethane. Evaporation of the organic solvent gave a sticky yellow solid, which was further purified by flash chromatography (ethyl acetate), followed by overnight stirring with 10 ml ether to remove the last traces of DMF. Filtration of the suspension and drying in vacuo gave a bright yellow powder (920 mg, 93%). M.p. 179-181° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz), 4.42 (q, J=7 Hz), 7.51 (dd, J=7 Hz, J=7 Hz, 1H), 8.06 (dd, J=7, J=7 Hz, 1H), 8.80 (s, 1H), 9.57 (d, J=7 Hz), 9.90 (s, 1H). MS: m/z 245.0683; required for C13H11NO4: 245.0688.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:13]([O-])(=O)=O.[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[I:13][C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:2][CH:3]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C1(c2ccc(I)cc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 106 %

Procedure:
A mixture of 1-phenylcyclopropane carboxylic acid (16.5 g, 101 mmol), sodium iodate (5.04 g) and concentrated sulfuric acid (1 mL) in acetic acid (70 mL) was stirred and heated at 70° C. for 2 days. Additional sodium iodate (1.88 g) and sulfuric acid (1 mL) were added, and stirring was continued for 1 day. The acetic acid was evaporated, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium thiosulfate, dried, filtered, and evaporated. The solid residue was recrystallized form methanol/water to give 1-(4-iodophenyl)cyclopropane-1-carboxylic acid (7.98 g, 27 mmol, 27%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]#[C:29][C:30]4([CH3:34])[CH2:33][O:32][CH2:31]4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:34][C:30]1([C:29]#[C:28][C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:16]4)[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:39]5[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=5)[CH:3]=4)[O:8][C:9]3=[CH:10][CH:11]=2)[CH2:31][O:32][CH2:33]1
Reactant: CC1(C#Cc2ccc3c(c2)[C@@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(Br)cnc2O3)COC1
Reactant: Cc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(C#CC4(C)COC4)ccc2O3)cn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A vial was charged with (S)-tert-butyl 3-bromo-7-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.054 g, 0.10 mmol), 6-methylpyridin-3-ylboronic acid (0.041 g, 0.30 mmol), potassium carbonate (0.069 g, 0.50 mmol), and Pd(AmPhos)2Cl2 (7.05 mg, 9.95 μmol). The vial was flushed with Ar (g), then dioxane (0.66 mL) and water (0.33 mL) were added in sequence. The vial was sealed and heated at 80° C. for 16 h. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography on silica gel (0-75% EtOAc:Hex) to afford (S)-tert-butyl 7-((3-methyloxetan-3-yl)ethynyl)-3-(6-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.027 g, 0.049 mmol, 48.9% yield) as a white solid. MS m/z=555.3 [M+H]+. Calculated for C31H30N4O4S: 554.20.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].O[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])=[CH:17][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of N-(2-hydroxyethyl)phthalimide (3.59 g, 18.75 mmol), 4-hydroxybenzotrifluoride (3.04 g, 18.75 mmol), diethyl azodicarboxylate (4.37 ml, 28.13 mmol) and triphenylphosphine (7.38 g, 28.13 mmol) in THF (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to afford N-[2-(4-trifluoromethylphenoxy)ethyl]phthalimide (4.05 g, yield 69%) as a colorless crystalline powder.
Reaction SMILES: [BrH:1].C(O)(=O)C.O=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:8][S:9][C:10]#[N:11].O>C(O)(=O)C>[Br:1][C:10]1[S:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1
Reactant: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A 25% hydrogen bromide/acetic acid (35 ml) solution was added to a solution of 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl thiocyanate (3.88 g, 15.8 mmol) in acetic acid (35 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.88 g (59.1%) of the desired product as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=C)[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.C[OH:17]>>[OH:1][CH2:2][C@H:3]1[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][C:6](=[O:17])[CH2:7]1
Reactant: CO
Reactant: C=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Product: O=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane from Step C (1.87 g, 9.0 mmol) in methanol (75 mL) was cooled in a dry ice/acetone bath and ozone was bubbled into the solution until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to rt over 2 h. The mixture was treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 h before most of the methanol was removed in vacuo. The mixture was diluted with water and extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (50% ethyl acetate in hexanes) to give the title compound (1.87 g), [α]D=+132 (MeOH, c=1.2).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)O2
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1
Yield: 38.9 %

Procedure:
By using 5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (4.02 g, 15.8 mmol) synthesized in Reference example 53 and 1-(4-methoxyphenyl)piperazine (6.08 g, 31.6 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 2.25 g (yield 39%).
Reaction SMILES: [C:1](O)(=[O:3])C.[C:5]([O:9][C:10](=[O:32])[N:11]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([CH2:30][NH2:31])[N:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[C:5]([O:9][C:10](=[O:32])[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])[C:23]1[CH:28]=[CH:27][C:26]2[NH:29][C:1](=[O:3])[NH:31][CH2:30][C:25]=2[N:24]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3)c(OC)c1
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester acetate salt (1.3 g, 2.56 mmol) and N,N-diisopropylethylamine (890 μL, 5.12 mmol, 2 equiv) in THF (20 mL) was added a solution of 1,1′-carbonyldiimidazole (622 mg, 3.84 mmol, 1.5 equiv) and the reaction mixture was stirred overnight. The solvent was evaporated and the crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 50-100%) to afford (2,4-dimethoxy-benzyl)-(2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (464 mg). MS: [M+H]+=415
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
7-bromo-2(1H)-quinoxalinone (47.2 g; 210 mmol) was added to phosphorus oxychloride (470 mL). The reaction mixture was stirred at 100° C. for 2 hours, cooled down to room temperature and evaporated to dryness. The crude product was taken up into DCM and poured onto ice, water and K2CO3 powder. The mixture was filtered over celite. The celite was washed twice with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness to give 49 g (96%) of 7-bromo-2-chloro-quinoxaline (grey solid). MP=146° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.25 g), ethyl 4-hydroxy-2-phenylpyrimidine-5-carboxylate (1.50 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 0.2N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were recrystallized from tetrahydrofuran-ethyl acetate to give ethyl 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylate as colorless prism crystals (2.50 g, yield 75%). melting point: 142-143° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C:6](=[O:8])[CH3:7].[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][C@H:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)CCC[C@H](C)CCCC(C)C
Yield: 23.6 %

Procedure:
A solution of 33.6 g (3E,6R)-6,10-dimethyl-3,9-undecadien-2-one in one liter of ethyl acetate was hydrogenated over Raney-Nickel (2 g) during 21 hours (hydrogen uptake 10.7 l). Thereafter, the catalyst was filtered off and the filtrate was concentrated. According to gas chromatography the crude product (34) contained 77% (R)-6,10-dimethyl-2-undecanone. 15 g of the crude product (44% of the total amount) were chromatographed on silica gel (n-hexane/ethyl acetate). After distillation of the pure fractions there were obtained 8.1 g (R)-6,10-dimethyl-2-undecanone (99.8% purity according to gas chromatography). The enantiomeric purity was 96.6% ee, as determined by gas chromatographic diastereomer analysis of an acetal derivative with an optically active diol. This enantiomeric purity corresponds to that of the used starting material.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[O:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].[H-].[Na+].[CH3:23]I>CN(C=O)C>[N:1]([CH:4]1[CH:5]([O:20][CH3:23])[CH2:6][O:7][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1COC(c2c([N+](=O)[O-])cnn2C)CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol, (Intermediate 57) (182 mg, 0.65 mmol) in anhydrous DMF (5 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) portionwise over 10 min. After a further 45 min, methyl iodide (0.06 mL, 0.97 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. Further sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added followed by methyl iodide (0.06 mL, 0.97 mmol) and the mixture stirred at room temperature for 48 hr. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-(5-azido-6-methoxyoxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as an oil (100 mg). A solution of this oil (100 mg, 0.37 mmol) in THF/water (5 mL/1 mL) was treated with triphenylphosphine (97 mg, 0.37 mmol) and the reaction mixture heated at 70° C. behind a blast shield for 18 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (3 mL) at 0° C. and di-tert-butyl-dicarbonate (89 mg, 0.4 mmol) and DIPEA (0.18 mL, 1.02 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 3 hr. Water (10 mL) was added and the mixture extracted with DCM (20 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave racemic tert-butyl-(3-methoxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (relative stereochemistry as shown above) as a clear oil (119 mg, 47% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.39 (dd, J=10.6, 3.6 Hz, 1H), 4.75 (br s, 1H), 4.33 (dd, J=14.2, 1.9 Hz, 1H), 4.06 (s, 3H), 3.91-3.83 (m, 1H), 3.75 (dd, J=14.2, 3.2 Hz, 1H), 3.43 (s, 3H), 3.39-3.34 (m, 1H), 2.22-2.12 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.82 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:13][C:14]([C:21](O)=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=1>>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:30]=[CH:31][C:32]([NH:35][C:21]([C:14]2[O:13][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:16][C:15]=2[C:17]([F:18])([F:19])[F:20])=[O:22])=[CH:33][CH:34]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: COCCOc1ccccc1-c1nc(C(F)(F)F)c(C(=O)O)o1
Product: COCCOc1ccccc1-c1nc(C(F)(F)F)c(C(=O)Nc2ccc(N(C)CCOC)nc2)o1

Procedure:
With a procedure similar to example 1 above, 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C23H25F3N4O5 (m/e) 494, obsd 495 (M+H).