Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1.[CH2:36]([C:42]1[S:43][C:44]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52](O)[CH:53]=3)[CH:48]=2)=[N:45][N:46]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[CH2:36]([C:42]1[S:43][C:44]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([O:8][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:53]=3)[CH:48]=2)=[N:45][N:46]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCc1nnc(-c2ccc3cc(O)ccc3c2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCC(=O)Oc1ccc2cc(-c3nnc(CCCCCC)s3)ccc2c1
Yield: 51.5 %

Procedure:
In a 30 ml-round-bottomed flask, 0.60 g (1.92 mM) of 2-hexyl-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole, 0.25 g (1.92 mM) of heptanoic acid were dissolved in 10 ml of dichloromethane. Under stirring, 0.39 g (1.89 mM) of N,N'-dicyclohexylcarbodiimide and 0.02 g of 4-pyrrolidinopyridine were successively added the above solution at room temperature, followed by stirring for 8 hours at room temperature. After the reaction, precipitated N,N'-dicyclohexylurea was filtered off and the filtrate was dried off under reduced pressure to obtain a solid. The solid was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/1) and recrystallized from a mixture solvent (ethanol-ethyl acetate) to obtain 0.42 g of 2-hexyl-5-(6-heptanoyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 81.5 %). ##STR139##
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccc(F)cc2F)cc1=O
Yield: 53 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,4-difluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,4-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10 g, 53%) as a white solid; ESI-MS 364 [M+H+]; HPLC: >98% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.89-7.90 (d, 1H), 7.15-7.21 (m, 1H), 6.94-7.05 (m, 2H), 5.94 (s, 1H), 5.50-5.55 (m, 1H), 2.30-2.40 (m, 1H), 2.09-2.16 (m, 1H), 1.50-1.79 (m, 7H), 1.14-1.21 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30](O)=[O:31])[CH:4]=[N:3]1.[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].CCN=C=NCCCN(C)C.Cl.O>O1CCCC1.ClCCl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30]([NH:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:31])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1ncc(NC(=O)CC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)CC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a suspension of 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoic acid (600 mg) and tert-butyl (2-aminoethyl)carbamate (240 mg) in tetrahydrofuran (12 ml) and dichloromethane (6 ml) was added WSCD HCl (522 mg), and the whole mixture was stirred at room temperature overnight. To the reaction mixture was added water (3 ml), and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate. The evaporation of the solvent gave a crude residue, which was triturated with diisopropyl ether-ethyl acetate (2:1) to give tert-butyl {2-[(3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoyl)amino]ethyl}carbamate (537 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18].Cl.[OH-].[Na+]>O.C(O)C>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH:18][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2c(C)cccc2C)nc(-c2ccccn2)n1
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol), 2,6-dimethylaniline (45 μl, 0.365 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (75 ml), which was washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow oil (58 mg, 82%). 1H NMR (CDCl3): 8.81–8.78 (m, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.83–7.77 (m, 1H), 7.36–7.30 (m, 1H), 7.21–7.13 (m, 3H), 6.91 (s, 1H), 5.77 (s, 1H), 2.39 (s, 3H), 2.23 (s, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>>[CH3:1][C@@H:2]1[N:7]([C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 49.9 %

Procedure:
The procedures described in Example 104 and starting with (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) and 5-bromo-2-nitropyridine (10.5 g, 50 mmol) afforded 113a as a yellow solid (8.05 g, 50%). See FIG. 13. MS-ESI: [M+H]+ 323
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)=[N:17][CH:18]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@H]1CC[C@H](Nc2ccc(Br)cn2)CC1
Temperature: 130 °C

Procedure:
A mixture of trans-4-aminocyclohexanecarboxylic acid hydrochloride (2.00 g, 11.1 mmol), 5-bromo-2-fluoropyridine (2.29 mL, 22.3 mmol), potassium carbonate (3.08 g, 22.3 mmol), DIEA (3.89 mL, 22.3 mmol) in NMP (50 mL) was heated to 130° C. overnight. The reaction was cooled to room temperature, filtered through a pad of CELITE, and washed with NMP (50 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2/MeOH, 0-10%) to afford trans-4-[(5-bromopyridin-2-yl)amino]cyclohexanecarboxylic acid as a off-white solid. MS ESI calc'd for C12H16BrN2O2 [M+H]+ 299 and 301. found 299 and 301.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]=2[CH3:20])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH3:20])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2nc(C(C)(C)C)cs2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)cs1

Procedure:
Methyl 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoate (Step A, 7.3 g, 25.2 mmole) was stirred with lithium hydroxide (1.5 g, 63.5 mmol) in 20 mL of 1,4-dioxane and 10 mL of water for 3 hours. It was concentrated to dryness to collect 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoic acid as a white solid. This was used in the next step without any further purification. LCMS (M+H)+: 276.0
Reaction SMILES: C(OC([NH:8][C@H:9]([C:19]([O:21][CH3:22])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([C:19]([O:21][CH3:22])=[O:20])[NH2:8])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Yield: 84 %

Procedure:
The same procedures as in Example 29 were carried out from the compound obtained in Example 32 (50.6 g), 4 mol/L of hydrogen chloride-dioxane (123 mL), and methylene chloride (400 mL), to give the captioned compound (33.7 g, 84%) as crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Br[C:20]1[CH:21]=[C:22]([C:27]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[C:29]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:28]=2)[CH:23]=[C:24](Br)[CH:25]=1.C([O-])([O-])=O.[K+].[K+].[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]3[CH:21]=[C:22]([C:27]4[N:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:30]=[C:29]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:28]=4)[CH:23]=[C:24]([C:60]4[CH:59]=[CH:58][C:57]([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=5)=[CH:62][CH:61]=4)[CH:25]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)c2ccccc2-c2ccc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4nc(-c5ccccc5)cc(-c5ccccc5)n4)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
In a stream of argon, 0.71 g (3 mmol) of 9,9-dimethyl-2-fluoreneboronic acid, 1.4 g (3 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenylpyrimidine and 34.7 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 115 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 50° C. To the suspension, 9 mL (9 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 18 hours. The resultant reaction mixture was cooled to room temperature, and then, 0.896 g (4.5 mmol) of 4-(2-pyridyl)phenylboronic acid and 9 mL (9 mmol) of an aqueous 1M K2CO3 solution were added to the reaction mixture. The resultant mixture was heated to 60° C., and maintained at that temperature for 3.5 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.85 g of the target 2-[5-(9,9-dimethylfluoren-2-yl)-4′-(2-pyridyl)biphenyl-3-yl]-4,6-diphenylpyrimidine as a white solid (yield: 43.3%).
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH3:8].[F:22][C:14]1[CH:13]=[C:12]2[C:17]([N:18]3[C@H:10]([CH2:11]2)[CH2:9][NH:8][CH2:20][C@H:19]3[CH3:21])=[N:16][CH:15]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H]2Cc3cc(F)cnc3N21
Product: N
Yield: 150.5 %

Procedure:
A solution of 0.138 g (4R,9aR)-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 1.5 mL trifluoroacetic acid was kept at room temperature for 1 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:sat. ammonia (9:1:0.1) to yield 0.070 g (4R,9aR)-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene as slightly yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=1[OH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:30][C:24]1[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=1[NH:22][C:17]([C:15]1[O:14][N:13]=[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[CH:16]=1)=[O:19]
Reactant: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Reactant: Nc1cc(O)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](COc1cc(C(=O)Nc2cc(O)ccc2O)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
To a solution of 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylic acid (1.5 g), 2-aminobenzene-1,4-diol hydrochloride (0.847 g) and HATU (1.99 g) in DMF (20 mL) was added N,N-diisopropylethylamine (1.80 mL), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, 0.1M hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.11 g).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9](SC)[C:10]3[C:11](=[CH:13][S:14][CH:15]=3)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([N:31]3[CH2:32][CH2:33][N:28]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30]3)[C:10]3[C:11](=[CH:13][S:14][CH:15]=3)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CSC1=Nc2ccc([N+](=O)[O-])cc2Nc2cscc21
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)Nc1cscc1C(N1CCN(Cc3ccccc3)CC1)=N2

Procedure:
A solution of 6-nitro 10-(methylthio)-4H-thieno [3,4-b] [1,5] benzodiazepine in excess N-benzylpiperazine and glacial acetic acid is heated at 140°-160°C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [C:1]([NH:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([NH:9][C:10]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:16][CH2:17]1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Reactant: BrCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
4-Benzoylureidopiperidine (1.28 g, 0.005 m), 2-(bromomethyl)naphthalene (1.1 g, 0.005 m) and triethylamine (0.6 g, 0.006 m) in dimethylformamide (25 cm3) were stirred at room temperature for 23 hours. Water was added and the precipitated solid filtered off and washed well with water. The solid was suspended in warm ethanol, acidified with ethanolic HCl and then heated until all the solid had dissolved. The title compound crystallised and was collected as the hydrochloride salt, hemihydrate (1.6 g), m.p. 232°-234° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[N+](C1C=CC=CC=1N)([O-])=O.BrBr.O>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]([F:18])([F:17])[CH:14]([F:15])[F:16]
Reactant: Nc1cc(Br)c(OC(F)(F)C(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: BrBr
Agent: Nc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)c(OC(F)(F)C(F)F)cc1N
Reaction time: 0.17 h

Procedure:
10.5 Grams of 5-bromo-2-nitro-4-(1',1',2',2'-tetrafluoroethoxy)aniline [i.e. the o-nitroaniline compound (VI) containing bromine as the substituent X] was dissolved in a mixed solvent of 25 ml of ethyl acetate and 25 ml of acetic acid. The resulting solution was dropwise added to a suspension of 5.0 g of iron powders in a mixed solution of 7 ml of acetic acid and 50 ml of water while maintaining the temperature at 45°-70° C. Thereafter, stirring was continued for 10 minutes within the same temperature range. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water in this order, dried over anhydrous magnesium sulfate and concentrated to obtain 9.5 g of 4-bromo-5-(1',1',2',2'-tetrafluoroethoxy) -1,2-benzenediamine. 1H-NMR (CDCl3): δ(ppm) 6.78(1H, s), 6.60(1H), 5.90(1H, tt, J=3, 52 Hz), 3.45(4H, broad)
Reaction SMILES: C(#N)C.[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](Br)[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:19][CH:18]=2)=[CH:13][CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Reactant: BrCC=Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCN(C/C=C/c2ccccc2)C1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an 8 ml acetonitrile solution of 300 mg of the compound (8) synthesized in Example 1 were added 234 mg cinnamyl bromide and 0.5 ml of triethylamine. This was then heated and refluxed for 3 hours. To the reaction mixture was added 10 ml of ice water. This was then extracted with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-referenced compound (18) in an amount of 320 mg (yield 73%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([N:9](C)[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:13]=[C:12]([C:26]([F:29])([F:28])[F:27])[N:11]=1)=O>C(O)C.Cl>[NH3:4].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:13]=[C:12]([C:26]([F:29])([F:27])[F:28])[N:11]=1
Reactant: Cc1[nH]cnc1C(=O)N(C)c1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]cnc1CNc1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Product: N
Yield: 110.7 %

Procedure:
A solution of crude (5-methyl-1H-imidazol-4-yl)methyl[4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2yl]formamide (0.27 g, 0.615 mmol) in ethanol (10 ml) and 2N hydrochloric acid (10 ml) was heated under reflux for 2 h. The solvents were then evaporated and the residue basified with 0.880 ammonia and extracted with DCM. The dried organic phase was evaporated onto silica gel and this mixture was purified on a silica gel SPE cartridge. Elution with DCM:ethanol:0.880 ammonia, 91:8:1, gave the title compound as a colourless crystalline solid (0.14 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.Cl.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)nc(N)n1
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (0.030 g, 0.106 mmol) in ethanol (5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.015 ml) followed by p-tolylamine (0.014 g, 0.127 mmol). After heating under reflux for 3.5 hours, the volatiles were evaporated under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred overnight. After filtration, the solid was dissolved in methanol (10 ml) and treated with aqueous sodium carbonate solution (1.0 M, 1 ml). After stirring for 0.5 hours, the volatiles were evaporated under reduced pressure, the solid was stirred with water (10 ml) for 15 minutes, and filtered to provide the title compound (0.020 g, 53% yield) as a white powder. 1H NMR (DMSO-d6) δ 1.37 (t, 3H, J=6.8 Hz, CH3), 2.27 (s, 3H, CH3), 4.12 (q, 2H, J=6.6 Hz, CH2), 6.25 (s, 2H, NH2), 6.75 (s, 1H, Ar), 7.10-7.14 (m, 3H, Ar), 7.40-7.42 (m, 1H, Ar), 7.55 (d, 2H, J=8.0 Hz, Ar), 7.92 (s, 1H, Ar), 9.05 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](S(C)(=O)=O)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH:35][C@H:36]1[C@H:40]2[O:41][CH2:42][CH:43]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C@H:39]2[O:38][CH2:37]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:35][C@H:36]3[C@H:40]4[O:41][CH2:42][C@@H:43]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C@H:39]4[O:38][CH2:37]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CCOC(=O)CC1CO[C@@H]2[C@H](O)CO[C@H]12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[[6-chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo-[4,5-b]pyridin-1-yl]-methoxy]ethyl-trimethyl-silane (357 mg, 0.694 mmol), ethyl 2-[(3aR,6R,6aR)-6-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (180 mg, 0.832 mmol), and DBU (150 uL, 0.995 mmol) in DMF (1.0 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (200 ml), washed with water (5×30 ml), brine (1×10 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give the title compound as a mixture of isomers. C34H40ClN3O6Si 649.24 observed m/e: 650.28 (M+H)+ (Rt 1.09 and 1.17/2 min)