Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([O:16]C)=[O:15])[CH2:9]1.[OH-].[Na+].Cl>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: COC(=O)C1C2CC(OC3CCCCO3)CC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C2CC(OC3CCCCO3)CC21

Procedure:
A mixture of 5 g. of methyl 3-[(tetrahydropyran-2-yl)oxy]-bicyclo[3.1.0]hexane-6-carboxylate (VIII, syn and anti, from Example 3), ethanol (45 ml.), and sodium hydroxide (10 ml. of a 20% aqueous solution) is refluxed for 20 minutes. Cooling evaporation of the ethanol under reduced pressure, and addition of 100 ml. of water gives a solution which is acidified with dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether extract is dried with anhydrous sodium sulfate and evaporated to give a mixture of exo syn and anti 3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]hexane-6-carboxylic acid.
Reaction SMILES: C(B1O[C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])O1)(C)=C.C(=O)([O-])[O-].[K+].[K+].ClC1C=[C:22]([C:35]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:36]=2)[C:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:24]C=1>O1CCOCC1.O>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][N:42]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=2)[C:37]2[N:36]=[C:35]([C:22]3[C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[N:24][CH:11]=[C:9]([C:6]([CH3:7])=[CH2:8])[CH:10]=3)[N:40]=[C:39]([CH3:41])[N:38]=2)=[CH:49][CH:48]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Yield: 91.5 %

Procedure:
A mixture of isopropenylboronic acid pinacol ester (0.119 mL, 0.633 mmol, Aldrich, St. Louis, Mo.), potassium carbonate (0.175 g, 1.267 mmol), (Amphos)2PdCl2 (0.022 g, 0.032 mmol) and 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 155, 0.185 g, 0.317 mmol) in 4:1 dioxane/water (2.5 mL) was heated in a sealed tube for 24 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol, 92% yield) as an orange solid. m/z (ESI, +ve ion) 590 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.71 (br. s., 1H); 8.94 (s, 1H); 8.44 (d, J=2.5 Hz, 1H); 8.27 (d, J=2.3 Hz, 1H); 7.91 (br. s., 1H); 7.22 range (m, 4H); 6.86 range (m, 4H); 6.73 (d, J=9.0 Hz, 1H); 5.33 (s, 1H); 5.01 (s, 1H); 4.89 (s, 2H); 4.82 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 2.59 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:64][CH2:65][CH2:66][NH:67][C:68](=[O:70])[CH3:69])[C:52]=1[CH3:71]>CN1C(=O)CCC1>[C:68]([NH:67][CH2:66][CH2:65][NH:64][C:53]1[N:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:11]([C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[C:52]=1[CH3:71])(=[O:70])[CH3:69]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CC(=O)NCCNc1nc(-c2ccc(Cl)cc2)nc(NCCN)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(-c2ccc(Cl)cc2)nc(NCCNC(=O)c2cc3ccccc3cn2)c1C
Reaction time: 12 h

Procedure:
A solution of 3-isoquinoline carboxylic acid (60 μl of a 0.3M solution in NMP), HATU (60 μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 20 min. N-{2-[6-(2-Aminoethylamino)-2-(4-chlorophenyl)-5-methylpyrimidin-4-ylamino]-ethyl}acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hrs. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 1 h

Procedure:
35.0 mg (0.095 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride, 19.7 mg (0.114 mmol) of N-t-butoxycarbonylglycine, 27.2 mg (0.142 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 1 mg (0.01 mmol) of 4-dimethylaminopyridine were dissolved in 1 ml of dichloromethane. 19.2 mg (0.190 mmol) of triethylamine was added to the obtained solution, and they were stirred for 1 hour. The product was purified by the silica gel chromatography (hexane:ethyl acetate=7:3 to 3:7) to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:18][CH2:19][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:4]3[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:27][CH:26]=2)=[O:24])[CH2:21][CH2:22]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@@H](C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 9.1 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 7 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (39 mg) was obtained.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 4-fluorobenzylamine (95 mg, 0.75 mmol). The title product was obtained as a pink solid (37 mg, 64% yield). 1HNMR (500 MHz, CDCl3) δ: 12.13 (1H, s), 7.90 (1H, t, J=5.50 Hz), 7.48 (1H, td, J=7.02, 1.83 Hz), 7.29–7.26 (3H, m), 7.06 (1H, t, J=7.33 Hz), 7.02–6.97 (3H, m),4.53 (2H, d, J=6.41 Hz), 3.81 (3H, s), 3.34 (3H, s). HRMS (ESI) calcd for C20H19FN3O4 (M+H): 384.1360; found: 384.1370.
Reaction SMILES: [H-].[Na+].I[CH:4]([CH3:6])[CH3:5].[N+:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]2[CH2:22][CH2:23][NH:24][C:25](=[O:26])[CH:18]2[CH2:17]1)([O-:9])=[O:8]>C1COCC1>[CH:4]([N:24]1[CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N+:7]([O-:9])=[O:8])[CH2:17][CH:18]2[C:25]1=[O:26])([CH3:6])[CH3:5]
Reactant: CC(C)I
Reactant: O=C1NCCN2CCN(c3ccncc3[N+](=O)[O-])CC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCN2CCN(c3ccncc3[N+](=O)[O-])CC2C1=O

Procedure:
NaH (15.87 mg, 0.3967 mmol) then 2-iodopropane (73.56 mg, 43.19 μL, 0.4327 mmol) were added to a solution of 2-(3-nitro-4-pyridyl)-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-9-one (100 mg, 0.3606 mmol) (prepared according to a procedure similar to Step 1 of Preparation N-1) in THF (5 mL) under N2. The reaction mixture was stirred at reflux for 24 h then it was partitioned between EtOAc and a saturated bicarbonate aqueous solution. Combined organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo to produce an oil that was used in next step without further purification. MS (ES+) 320.1.
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.O.[NH2:32][NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:32][NH2:33])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Product: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(NN)=N2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7,8-dimethyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepine-2-thione (411 mg, 1.0 mmol), hydrazine hydrate (60 mg, 1.2 mmol) and p-toluenesulphonic acid (10 mg) in n-butanol (5 ml) was heated at 100° C. for 1.5 hours. The solvent was removed under reduced pressure and the crude product was used directly for Examples 29-31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9](Br)=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[CH3:13][C:14]1[N:15]=[N:16][NH:17][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([N:17]2[CH:18]=[C:14]([CH3:13])[N:15]=[N:16]2)=[C:8]2[NH:7][CH:6]=[CH:5][C:4]=12
Reactant: COc1cnc(Br)c2[nH]ccc12
Reactant: Cc1c[nH]nn1
Product: COc1cnc(-n2cc(C)nn2)c2[nH]ccc12
Temperature: 130 °C
Reaction time: 17 h

Procedure:
4-Methoxy-7-bromo-6-azaindole (120 mg) was added in portions to a melted of 4-methyl-1,2,3-triazole (219 mg) under argon at 110-120° C. The mixture was heated to 130° C. and was stirred at 130° C. for 17 hours. The reaction mixture was cooled to room temperature and the resulting residue was purified by column chromatography using EtOAc/Hexane (6:4) mixture as eluent which afforded 4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine as a tan solid. 1H NMR (400 MHz, DMSO-D6): δ 2.38 (s, 3H), 4.01 (s, 3H), 6.66 (dd, 1H, J=2.9, 2.6), 7.53 (dd, 1H, J=2.9, 2.8), 7.70 (s, 1H), 8.62 (s, 1H), 11.78 (bs, 1H). MS: 230.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:39](=[O:41])[CH3:40])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A stirred solution of 6-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide (1.25 g, 99%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]([CH3:16])[CH2:10]2)[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:11]1[N:12]([CH3:15])[CH2:13][CH2:14][N:9]([C:6]2[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=2)[CH2:10]1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)[C@H](C)C2)n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N2CCN(C)[C@H](C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
To 4-chloro-6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.242 g, 0.94 mmol) in DMSO (3 mL) was added hydrazine monohydrate (2 mL). The reaction was stirred at room temperature for 3 days. Removed volatiles in vacuo and purified by RP-HPLC to provide 4-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as a yellow solid (0.079 g, 33%). LCMS: (M+H)+=255.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28]>>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:29])=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=S(=O)(Cl)c1cccs1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(S(=O)(=O)c3cccs3)CC1)O2

Procedure:
Compound 78 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, thiophene-2-sulfonyl chloride and conditions outlined in procedure P. M.p.=245-248° C.; 400 MHz 1H NMR (CDCl3) δ: 8.02-8.05 (m, 1H), 7.70-7.67 (m, 1H), 7.61-7.59 (m, 1H), 7.48-7.44 (m, 2H), 7.27-7.22 (m, 1H), 7.22-7.18 (m, 1H), 3.79-3.72 (m, 2H), 2.94 (s, 2H), 2.91-2.84 (m, 2H), 2.26-2.18 (m, 2H), 2.02-1.91 (m, 2H); LCMS: 448 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 0 °C

Procedure:
Commercially available 2-(3-bromophenyl)acetic acid (13 g 0.06 mol) was dissolved in ethanol (130 ml) and cooled to 0° C. Thionyl chloride (20 ml) was added drop wise. The mixture was heated to 85° C. over night. Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3, water, dried over anhydrous sodium sulfate and concentrated to give 13 g (88%) of A6.1a.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][CH:8]=2)=[C:14]([O:21][CH3:22])[CH:15]=1
Reactant: COc1cc(CO)ccc1OCc1coc(-c2ccco2)n1
Reactant: O=S(Cl)Cl
Product: COc1cc(CCl)ccc1OCc1coc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(4-([2-(2-Furyl)-1,3-oxazol-4-yl]methoxy)-3-methoxyphenyl)methanol (5.0 g) was added to thionyl chloride (5 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-1,3-oxazole as pale-brown crystals (3.95 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([NH2:15])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].O>COCCOC>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([NH:15][CH2:2][CH2:1][OH:3])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1cc(C(F)(F)F)c(N)cc1[N+](=O)[O-]
Reactant: C1CO1
Solvent: O
Solvent: COCCOC
Product: Nc1cc(C(F)(F)F)c(NCCO)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Ethylene oxide is passed in portions into a mixture of 2.2 g (10 mmol) of 1,4-diamino-2-nitro-5-trifluoromethylbenzene, 25 ml of water and 10 ml of monoethylene glycol dimethyl ether at 60° C. in the course of 20 minutes, and the reaction is monitored by thin layer chromatography. When the monohydroxyethylation is complete, the mixture is cooled slowly to room temperature and the precipitate is filtered off and washed with water.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])([O-:17])=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:23](=[O:24])[CH:22]([O:21][C:20]1[CH:28]=[CH:29][CH:30]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)[CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(Oc1cccc([N+](=O)[O-])c1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1cccc([N+](=O)[O-])c1)C(=O)NCc1ccccc1
Yield: 58.7 %

Procedure:
In 30 ml of toluene were dissolved 1.6 g (0.015 mole) of benzylamine and 1.2 g (0.015 mole) of pyridine, and thereto was added dropwise a solution of 3.1 g (0.013 mole) of 2-(3-nitrophenoxy)-butyroyl chloride in 30 ml of toluene at room temperature with stirring. Subsequently, after the same procedure as in Synthesis Example 7 was followed, the resultant crude crystals were recrystallized from ethanol to give 2.4 g of N-benzyl-2-(3-nitrophenoxy)-butyramide melting at 114°~116° C. as pale yellow needles.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 6 h
Yield: 75.9 %

Procedure:
A solution of 0.1 mol (21.4 g) of 4'-hydroxybiphenyl-4-carboxylic acid and 0.11 mol (19.9 g) of tetramethylammonium hydroxide (pentahydrate) in 200 ml of DMF was stirred for 2 hours. To this was then added 0.1 mol (17.1 g) of benzyl bromide and the mixture was stirred for 6 hours. The reaction solution was extracted with ether and the extract was dried and concentrated. The resulting crude product was purified by column chromatography to obtain 23.1 g of the objective ester compound of the following formula. (yield: 76%) ##STR98##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:20]([C:16]4[NH:15][CH:19]=[CH:18][CH:17]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=Cc1ccc[nH]1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccc[nH]4)nc3cc21

Procedure:
Analogously to Example 2, from 3.8 g. (20 mmol) 5,6-diamino-3,3-dimethylindolin-2-one, 1.9 g. (20 mmol) pyrrole-2-aldehyde and 0.4 g. (2 mmol) p-toluenesulphonic acid, after acidification and evaporation of the reaction mixture, there is obtained the crude product of the title compound. For purification, the residue is worked up with water and the filtrate is neutralised with 2N aqueous ammonia solution and filtered off with suction. The residue is recrystallised from isopropanol with the addition of ethanolic hydrochloric acid. The yield is 1.2 g. (20% of theory); m.p. of the hydrochloride >300° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](OC(=O)c2ccccc2)C[C@H]1C=C(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.33 g), triphenylphosphine (0.52 g) and benzoic acid (0.24 g) in tetrahydrofuran (4 ml) was added diethyl azodicarboxylate (0.31 ml) at ambient temperature. After stirring at ambient temperature for 1 hour, the solution was evaporated. To the residue was added a mixture of n-hexane and ethyl acetate (2:1 V/V), and precipitated triphenylphosphine oxide was filtered off. The filtrate was evaporated, and the residue was chromatographed on silica gel (80 ml) eluting with a mixture of n-hexane and ethyl acetate (8:2-7:3 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-benzoyloxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.42 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24].O>ClCCl>[Br:15][C:16]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([F:22])=[C:20]([C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([F:5])[CH:7]=2)=[O:10])[CH:21]=1
Reactant: COc1cc(F)ccc1Br
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1Br
Temperature: -60 °C

Procedure:
A total of 716 mg of aluminium chloride was suspended in 24.4 ml of dichloromethane and was then mixed with 0.65 ml of 3-fluorobenzoyl chloride and 1 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a under stirring at −60° C. The mixture was raised in temperature to room temperature over 2.5 hours and was stirred for further 3 hours. Water was added to the reaction mixture under ice-cooling, followed by extracting with diethyl ether. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 856 mg of the title compound as white crystals.