Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C2C(N(O)N=NC2=CC=1)=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:28]([C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C@@H:29]([C:42]([NH:44][C@H:45]([C:53]([OH:55])=O)[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[NH2:66][C@@H:67]([C:80]([NH:82][C@H:83]([C:91]([NH:93][CH2:94][C:95]([O:97][CH3:98])=[O:96])=[O:92])[CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)=[O:81])[CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74].S(O)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[NH:28]([C:56]([O:58][CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:57])[C@@H:29]([C:42]([NH:44][C@H:45]([C:53]([NH:66][C@@H:67]([C:80]([NH:82][C@H:83]([C:91]([NH:93][CH2:94][C:95]([O:97][CH3:98])=[O:96])=[O:92])[CH2:84][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)=[O:81])[CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:73]([O:75][C:76]([CH3:78])([CH3:77])[CH3:79])=[O:74])=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36]
Reactant: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.6 g of HOOBt, 1.3 g of NEM and 2.2 g of DCC are added to 5.3 g of Z-D-Lys(Boc)-Phe-OH and 6.4 g of H-D-Lys(Boc)-Phe-Gly-OMe, TosOH in 100 ml of DMF, with stirring. After the mixture has been left to stand overnight and the urea has been filtered off, the solvent is distilled off in vacuo. The residue is taken up in 300 ml of ethyl acetate/n-butanol (2:1), the mixture is washed, as above, with citric acid solution, sodium bicarbonate solution and water and dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is recrystallized from 60 ml of isopropanol.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[C:4](=[O:24])[N:3]1[CH:25]([CH:30]([CH3:32])[CH3:31])[C:26]([NH:28][OH:29])=[O:27].[OH:33][NH2:34].Cl.CN1CCOCC1>C(Cl)(Cl)Cl.CO.CC(O)=O>[OH:29][NH:28][C:26](=[O:27])[CH:25]([N:3]1[C:4](=[O:24])[CH:5]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15](=[N:34][OH:33])[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[NH:6][C:2]1=[O:1])[CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)C(C(=O)NO)N1C(=O)NC(CCc2ccc(C(=O)Cc3ccccc3)cc2)C1=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NO)N1C(=O)NC(CCc2ccc(C(Cc3ccccc3)=NO)cc2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution compound 40 (140 mg, 0.32 mmol) in CHCl3/CH3OH (10 mL) was added HONH2×HCl (44 mg, 0.64 mmol) and N-methylmorpholine (0.071 mL, 0.64 mmol). After stirring for 5 min, one drop of CH3COOH was added and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was purified by preparative thin layer chromatography to afford the title compound as a white solid (20 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Cl:16])=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9].S(Cl)([Cl:19])=O>>[Cl:16][C:6]1[C:5]([O:4][CH2:3][CH2:2][Br:1])=[C:13]([O:14][CH3:15])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:19])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c(Cl)c1OCCBr
Product: COc1ccc(C(=O)Cl)c(Cl)c1OCCBr
Temperature: 60 °C
Yield: 100 %

Procedure:
A suspension of 3-bromoethoxy-2-chloro-4-methoxybenzoic acid (1.4 g, 4.5 mmol) in thionyl chloride (20 ml) is heated at 60 ° C. until dissolved (˜20 min) plus an additional 30 minutes. The reaction mixture is cooled to room temperature and excess thionyl chloride is evaporated under reduced pressure. The resulting residue is evaporated at reduced pressure with toluene (50 ml) two times to obtain 1.5 g (100%) of 2-chloro-3-bromoethoxy-4-methoxybenzoic acid chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7](CC(C)C)[CH:6]=[C:5](C(F)(F)F)[C:4]=1[OH:17].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C>C1C=CC=CC=1>[O:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=[N:1][CH2:18]1.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)Cc1cc(CN)c(O)c(C(F)(F)F)c1
Solvent: CCCCCCCCCC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C1=NCOc2ccccc21
Reaction time: 3 h

Procedure:
A solution of 2-aminomethyl-4-(2,2-dimethylethyl)-6-trifluoromethylphenol (1.24 g., 0.005 mole), 2-oxotricyclo(3.3.1.1.3,7)decane (0.75 g., 0.005 mole) and acetic acid (0.25 ml.) in dry benzene (50 ml.) is refluxed under a constant water separator for 3 hr. The solution is cooled, washed with 2% sodium hydroxide solution, water and salt brine and then dried (MgSO4) and evaporated under reduced pressure. The solid residue (1.2 g.) is crystallized from hexane to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-trifluoromethylspiro[2H-1,3-benzoxazine-2,2'-tricyclo(3.3.1.1.3,7)decane] (0.65 g.), m.p. 125°-126.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Temperature: 70 °C
Yield: 74.1 %

Procedure:
A solution of m-nitrophenol (2.0 g, 14 mmol), 2-bromoethanol (1.4 mL, 20 mmol), and potassium carbonate (3.0 g, 22 mmol) in N,N-dimethylformamide (10 mL) was heated at 70° C. for 7 h. The reaction mixture was treated with additional 2-bromoethanol (0.5 mL, 7.2 mmol) and potassium carbonate (1.0 g, 7.2 mmol) and heated at 70° C. for 20 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude residue. This material was purified by flash column chromatography to give the desired product (1.9 g, 70%) as a white solid. LCMS for C8H10NO4 (M+H)+: m/z=183.9.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.P(Cl)(Cl)([Cl:25])=O>C(#N)C>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Temperature: 80 °C

Procedure:
Methyl 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoate (2.85 g, 9.68 mmol) was suspended in acetonitrile (19.4 mL), cooled to 0° C. to which phosphorus oxychloride (1.81 mL, 19.4 mmol) was added dropwise. The reaction mixture was warmed to 80° C. for 2.5 h, then concentrated, diluted with 150 mL of ethyl acetate, added to a separatory funnel and partitioned with water. The organics were washed 2×50 mL with water, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 313(M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](/[CH:8]=[CH:9]/[C@H:10]([CH:33]([CH3:35])[CH3:34])[CH2:11][C@@H:12]1[O:16]C(C)(C)[N:14](C(OC(C)(C)C)=O)[C@H:13]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:7])[CH2:2][CH2:3][CH3:4].Cl>CO>[NH2:14][C@@H:13]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[C@@H:12]([OH:16])[CH2:11][C@@H:10]([CH:33]([CH3:34])[CH3:35])/[CH:9]=[CH:8]/[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7]
Reactant: CCCCNC(=O)/C=C/[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Agent: Cl
Solvent: CO
Product: CCCCNC(=O)/C=C/[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
0.53 g (1.07 mmol) of t-butyl (4S,5S)-5-[(S,E)-4-(butylcarbamoyl)-2-isopropyl-3-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate is dissolved in 18.2 ml of methanol and treated at 10° with 6.4 ml of 3.88M hydrochloric acid in methanol. The reaction mixture is subsequently stirred at room temperature for 5 hours and thereafter evaporated. The residue is dissolved in methylene chloride and the methylene chloride solution is washed with 2N sodium bicarbonate solution, dried over potassium carbonate and evaporated under reduced pressure. In this manner there is obtained 0.314 g of (E,4S,6S,7S)-7-amino-N-butyl-8-cyclohexyl-6-hydroxy-4-isopropyl-2-octenamide as an oil which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: FC(F)(F)c1ccc(Br)cn1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(C(F)(F)F)nc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-trifluoromethylpyridine.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([S:31][CH2:32][CH2:33][CH3:34])[N:25]=1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:30][C:29]3[C:24]([CH3:23])=[N:25][C:26]([S:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CCCSc1ccc(N)c(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CCCSc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2OC)c(C)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (0.966 g, 2.93 mmol), 2-methyl-6-propylsulfanyl-pyridin-3-ylamine (0.545 g, 2.99 mmol), palladium acetate (0.0375 g, 0.167 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.119 mL, 0.335 mmol), and sodium 2-methylpropan-2-olate (0.422 g, 4.39 mmol) in 15 mL dioxane was heated under microwave irradiation at 120° C. After 2 h, mixture was purified by HPLC; fractions containing pure product were collected, partly concentrated, and residue was extracted with CH2Cl2 and 1M NaOH. Organic phases were dried over MgSO4, filtered, and concentrated to give 4-[5-methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a thick oil (0.509 g, 36%). 1HNMR (MeOH-d4, 400 MHz) δ 1.00-1.04 (t, J=7.3 Hz, 3H), 1.23-1.24 (d, J=6.2 Hz, 6H), 1.66-1.78 (m, 4H), 1.96-2.02 (m, 2H), 2.37 (s, 3H), 3.06-3.10 (t, J=7.3 Hz, 2H), 3.36-3.42 (m, 2H), 3.71-3.77 (m, 2H), 3.88 (s, 3H), 4.81-4.87 (m, 1H), 5.28-5.34 (m, 1H), 7.09-7.11 (d, J=8.3 Hz, 1H), 7.57-7.59 (d, J=8.3 Hz, 1H), 7.84 (s, 1H). Exact mass calculated for C23H33N5O4S 475.23 found 476.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH:17]=[CH:16][C:15]=1[S:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1>C(O)C>[CH3:24][C:22](=[CH2:23])[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Solvent: CCO
Product: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 234a (55 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (12 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.76 (s, 3H) 2.02 (s, 3 H), 2.75 (s, 3 H), 4.52 (s, 2 H), 4.98 (s, 1 H), 5.05 (s, 1 H), 6.30 (d, J=7.35 Hz, 1 H), 7.04-7.19 (m, 4 H), 7.36 (s, 1 H), 7.41 (d, J=8.46 Hz, 2 H) 7.78 (d, J=8.82 Hz, 1 H), 8.37 (d, J=6.99 Hz, 1H), 8.94 (d, J=8.46 Hz, 1 H) 9.97 (s, 1 H), 10.99 (s, 1 H), 14.33 (s, 1 H); MS (ESI+) m/z 471(M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[N:19]1([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:32]=[C:33]([CH2:35][O:36][C:37]5[CH:46]=[CH:45][C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[N:38]=5)[N:34]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1ccc2nc(OCc3cn4c(-c5ccc(N6CCNCC6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 47a (144 mg, 0.240 mmol) in DCM (1 mL) was added TFA (0.8 mL). The resulting mixture was stirred at rt for 1 h and concentrated under reduced pressure. The residue obtained was dried under reduced pressure overnight, suspended in 20 mL of diethyl ether, sonicated for 5 min and concentrated. The solid obtained was dried under reduced pressure for 4 h to obtain a residue which was dissolved in 1:1 MeOH/DCM solution (5 mL) and filtered through a sodium bicarbonate cartridge. The filtrate was concentrated under reduced pressure and the resulting residue was triturated in ether to give compound 47b. Mass Spectrum (LCMS, ESI pos.) Calcd. for C29H30N8O2: 523.2 (M+H). Found 523.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].[Cl:14][C:15]1[C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[N:19][CH:18]=[CH:17][N:16]=1>>[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][CH2:3][CH2:2][NH:1][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:20]1[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=1)(=[O:8])[NH2:9]
Reactant: NCCOc1ccccc1C(N)=O
Reactant: Clc1nccnc1OCC1CO1
Product: NC(=O)c1ccccc1OCCNCC(O)COc1nccnc1Cl

Procedure:
Analogously to the process described in Example 23, 9.0 g of 2-(2-aminoethoxy)-benzamide and 9.3 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine give 1-[2-(2-carbamoyl-phenyloxy)-ethyl-amino]-3-(2-chloro-3-pyrazinyloxy)-2-propanol, melting point 132°-133° C. The neutral fumaric acid salt prepared therefrom using the calculated amount of fumaric acid crystallises from a mixture of methanol and diethyl ether, melting point 167°-168° C.
Reaction SMILES: [C:1]([C:8]([O:10][CH2:11][CH3:12])=[O:9])#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].Cl>C1(C)C(C)=CC=CC=1.C(=[Co](=C=O)C1C=CC=C1)=O>[CH2:17]1[C:18]2[C:14](=[CH:13][C:1]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:19]=2)[CH2:15][CH2:16]1
Reactant: C#CCCCC#C
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: O=C=[Co](=C=O)C1C=CC=C1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c(cc1C(=O)OCC)CCC2
Temperature: 80 °C
Reaction time: 120 h
Yield: 21.8 %

Procedure:
Diethyl acetylenedicarboxylate (1.0 ml, 6.3 mmol) and dicarbonylcyclopentadienylcobalt (0.1 ml, 0.62 mmol) were added dropwise to a solution of 1,6-heptadiyne (0.72 ml, 6.3 mmol) in xylene (5 ml), and stirred at 80° C. for 5 days. To the reaction solution was added dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, followed by purifying the residue by silica gel chromatography (chloroform, successively hexane:ethyl acetate=10:1) to give 0.36 g of diethyl 5,6-indandicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[OH:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(O)C1CCCCC1
Yield: 83 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-chlorophenyl)-2-methyl-3-furaldehyde (1.7 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (15 mL) to give the title compound (2.0 g, 83%) as a white crystal.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16](Cl)=[O:17])=[C:4]2[CH:3]=[CH:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:32])[CH2:28][N:29]([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:31][N:29]([CH3:30])[CH2:28][CH:27]([NH:32][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:17])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: COc1ccccc1C(N)CN(C)C
Reactant: O=C(Cl)c1sccc1Nc1ccnc2[nH]ccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(CN(C)C)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Yield: 14.4 %

Procedure:
To a 40-mL vial with magnetic stir bar at 25° C. under a nitrogen atmosphere was added 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl chloride (0.26 g, 0.94 mmol) and anhydrous DCM (8 mL). 1-(2-Methoxy-phenyl)-N*2*,N*2*-dimethyl-ethane-1,2-diamine (0.2 g, 1.0 mmol) was then added followed by the diisopropylethylamine (0.6 g, 0.8 mL, 4.7 mmol) and stirring continued×16 hours. The solvent was evaporated under a nitrogen stream and the resulting residue purified via preparative HPLC (0.1% triethylamine/1% acetonitrile mixture in water and methanol) afforded the desired product as a white solid (59.1 mg, 14% yield). LCMS m/e 436 (M+H). 1H NMR (400 MHz, DMSO-d6) ppm 2.12 (s, 6H) 2.25 (dd, J=12.38, 4.27 Hz, 1H) 2.60 (dd, J=12.34, 9.78 Hz, 1H) 3.77 (s, 3H) 5.44-5.52 (m, 1H) 6.41 (dd, J=3.36, 1.18 Hz, 1H) 6.66 (d, J=5.44 Hz, 1H) 6.84 (td, J=7.42, 0.71 Hz, 1H) 6.92-6.97 (m, 1H) 7.16-7.22 (m, 1H) 7.24 (dd, J=7.57, 1.56 Hz, 1H) 7.26-7.28 (m, 1H) 7.39 (d, J=5.39 Hz, 1H) 7.81 (d, J=5.38 Hz, 1H) 7.98 (d, J=5.41 Hz, 1H) 8.23 (d, J=7.92 Hz, 1H) 9.89 (s, 1H) 11.49 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 65813.4 %

Procedure:
Nitrogen was bubbled through dioxane (800 mL) for 1 h followed by the addition of 4-chloro-2-(methyloxy)-1-nitrobenzene (61 g, 0.33 mol), 3-pyridinylboronic acid (Boron Molecular, 40 g, 0.33 mmol), dichloro(triphenylphosphine)palladium (10 g, 14 mmol), and degassed aqueous 3 N Na2CO3 (325 mL, 975 mmol). The reaction mixture was stirred with a mechanical stirrer and heated at 90° C. for 3 h. The reaction was cooled and most of the dioxane was removed in vacuo. It was diluted with water and then extracted with Ethyl acetate. Combined organic phases were dried (Mg2SO4), filtered and concentrated. The resultant solid was washed with diethyl ether to afford 4-(3-methoxy-4-nitrophenyl)pyridine (50 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.05 (s, 3 H), 7.53 (dd, J=8.4, 1.8 Hz, 1 H), 7.69 (d, J=1.8 Hz, 1 H), 7.84 (d, J=6.2 Hz, 2 H), 8.02 (d, J=8.4 Hz, 1 H), 8.72 (d, J=6.2 Hz, 2 H). ESIMS (M+H)+=231.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1N1CCOCC1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(2-methoxy-4-nitro-phenyl)-morpholine (1.0 g, 4.2 mmol, Step B) in EtOH (25 mL) at 20 ° C was added Pd/C (100 mg). The flask was capped with a rubber septum and H2 pressure was applied through a balloon/needle. The reaction mixture was stirred at 20° C. for 12 h, filtered through sand/Celite® and concentrated. Purification by chromatography of the crude mixture (97:3 CH2Cl2:MeOH) afforded 3-methoxy-4-morpholin-4-yl-phenylamine as a purple solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CCc1conc1-c1ccc(F)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1conc1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of methyl 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (1.68 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 15 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (1.49 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 40–41° C.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3](O)=[O:4].O.[NH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([NH2:33])=[O:4]
Reactant: N
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Solvent: O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(N)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and ammonia water (28% ammonia water).