Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][N:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC=C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC=Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,3-dip-tolyl-5,6-dihydropyrido[2,3-b]pyrazine (Example 8.2 step 1) (3.88 g, 12.38 mmol) in DCE (70 ml) was added ethyl 7-oxoheptanoate (6.40 g, 37.1 mmol) followed by sodium triacetoxyborohydride (10.4 g, 49.1 mmol). The reaction mixture was stirred for 2 days at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with water (70 ml) and extracted with EtOAc (3×70 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification using reverse phase chromatography eluting with MeCN/water (0.1% TFA) to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:30]([C:27]4[CH:26]=[N:25][C:24]([O:23][CH2:22][C:21]([F:33])([F:34])[F:20])=[CH:29][N:28]=4)=[O:31])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: O=C(O)c1cnc(OCC(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC(F)(F)F)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid (prepared as described in Suzuki Y. et al., WO 2009/091 016) following procedure G yielded the title compound as a colorless solid. MS: m/z=470.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21]([CH2:23]Br)=[O:22]>O>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21]([CH2:23][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:22]
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cooled slurry of 35 g. of imidazole in 25 ml. of dimethylformamide is added 24.9 g. of bromomethyl 2-naphthyl ketone. The mixture is stirred for 2 hours at 0° C., and then allowed to come to room temperature and stirred overnight. The solution is poured into water and the resulting sticky solid filtered off, washed with water and dissolved in benzene. Thereafter the resultant benzene solution is dried (azeotroped) to afford 1-(2-naphthoylmethyl)imidazole which is converted to its hydrochloride acid addition salt by addition of ethereal hydrogen chloride until precipitation is complete. The salt is crystallized by the addition of ethyl acetate and the resulting solid recrystallized from methanol/acetone to yield colorless needles of 1-(2-naphthoylmethyl)imidazole hydrochloride, m.p. 226°-228.5° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][CH2:23][C:24](Cl)=O.C(N(CC)CC)C>>[CH3:20][O:21][CH2:22][CH2:23][C:24]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCCC(=O)Cl
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Product: CCOC(=O)CCn1c(CCOC)nc2cnc3ccccc3c21

Procedure:
The method described in Part A of Example 12 was used to treat ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (9.82 g, 37.9 mmol, prepared in Part A of Example 18) with methoxypropionyl chloride (5.54 g, 45.4 mmol). The reaction with triethylamine (21.1 mL, 151 mmol) was heated at reflux for six hours and then subjected to the work-up procedure to provide 10.3 g of ethyl 3-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanoate.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C(O)C.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>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:6](=[O:7])[C:5]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[O:4][C:3]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC3(CCCC3)C2=O)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a stirred solution of 3-bromo-2-(4-methylsulfonylphenyl)-1-oxa-spiro[4,4]non-2-en-4-one (105 mg) in 5 ml of toluene and 15 ml ethanol, were added 20 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 50 mg of 4-isopropylbenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. The solvent was removed under reduced pressure and the resulting residue was extracted with 20 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo and the resulting crude product was purified by column chromatography (hexane/ethylacetate) to obtain 87 mg of 3-(4-isopropyl-phenyl)-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one as a solid. mp: 139-140° C. NMR: δ1.25 (s, 3H), 1.27 (s, 3H), 2.04 (m, 6H), 2.15 (m, 2H), 2.92 (m, 1H), 3.06 (s, 3H), 7.21 (m, 4H), 7.83 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). IR (cm−1): 2960, 1694, 1622, 1386, 1318, 1161, 768.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH2:22]2)[CH2:13][C@H:9]1[C:10]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:12])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C1CNCCN1
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCNCC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C of Example 1, was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. Piperazine (0.25 g, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (1.01 g, 93%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:29]O)[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:29]=[C:23]2[C:22]3[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=3)[NH:25][C:24]2=[O:28])=[CH:10][C:9]=1[F:15])[CH3:17]
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cc(F)ccc32)cc1F
Yield: 32.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (269 mg, 1.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (195 mg, 32%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(O)c1

Procedure:
A solution of 30.8 g (183 mmol) of 3-hydroxy-4-methoxybenzoic acid and 6 mL of conc sulfuric acid in 600 mL of methanol was refluxed overnight. Most of the solvent was removed and the remaining solution was poured into 600 mL of water containing 25 g of sodium bicarbonate. The product was extracted into ether, treated with Darco, dried and evaporated. The yield was 31.8 g of methyl 3-hydroxy-4-methoxybenzoate as pale yellow crystals.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([C:56](=[NH:71])[NH:57][C:58]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=3)=[O:59])[CH2:52][CH2:51]2)=[O:49])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([C:56](=[NH:71])[NH:57][C:58]([O:60][CH2:61][C:62]5[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=5)=[O:59])[CH2:52][CH2:51]4)=[O:49])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(C(=N)NC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 8 h
Yield: 76.9 %

Procedure:
1600 mg of 4-nitrobenzyl (1R, 5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R) -1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) were dissolved in 16 ml of dry acetonitrile, and a solution of 1120 mg of (2S,4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 93) in 11 ml of dry acetonitrile and 430 μl of diisopropylethylamine were added dropwise to the resulting solution, whilst ice-cooling. The resulting mixture was stirred at the same temperature overnight, after which it was concentrated by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dehydrated over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 300 ml), eluted with a 1 by volume mixture of acetonitrile and water. The fractions containing the desired compound were collected and concentrated by evaporation under reduced pressure, to obtain 1520 mg of the title compound, as a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([Sn](C)(C)C)=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>>[F:23][C:24]1[C:25]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[N:12]=[N:13][CH:14]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: COc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)cc1
Reactant: C[Sn](C)(C)c1ncc(F)cc1F
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4ncc(F)cc4F)c3)n2)cc1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine was coupled to 3,5-difluoro-2-trimethylstannylpyridine using the method of Example 6 to give 5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine, crystallised from hot 2-propanol as a pale yellow solid: δH (500 MHz, d6-DMSO) 3.88 (3H, s), 7.17 (2H, d, J 9.0 Hz), 7.69 (1H, t, J 9.1 Hz), 8.20 (1H, m), 8.52 (2H, d, J 9.0 Hz), 8.65-8.70 (2H, m), 8.77 (1H, d, J 2.2 Hz), 10.02 (1H, s); m/z (ES+) 395.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:19]=[N+:20]=[O:21]>S1(CCCC1)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]2)=[CH:6][C:7]=1[N+:20]([O-:21])=[O:19]
Reactant: O=[N+]=O
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc(C2(C(=O)O)CC2)cc1[N+](=O)[O-]

Procedure:
Commercially available 1-(4-methylphenyl)-1-cyclopropane carboxylic acid is treated with nitronium tetrafluoroborate in sulfolane to afford 1-(4-methyl-3-nitrophenyl)-1-cyclopropane carboxylic acid. This is converted to 1-(4-methyl-3-nitrophenyl)-1-bromocyclopropane by treatment with mercuric oxide and bromine in methylene chloride. Reduction with zinc dust in the presence of calcium chloride in aqueous ethanol affords 5-cyciopropyl-2-methylaniline. Conversion to 4-cyclopropyl-5-(2-imidazolinylamino)-7-methylbenzimidazole is completed in the same manner as 4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole (see Example 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 13.5 parts of 1-(2-aminophenyl)ethanone, 12.1 parts of N,N-diethylethanamine and 72 parts of benzene are stirred and cooled at 5°-10° C. Then there is added dropwise a solution of 18.2 parts of trichloroacetyl chloride in 36 parts of benzene while still cooling at 1°-10° C. Upon completion, stirring at that temperature is continued for 30 minutes. The reaction mixture is filtered, the filter-cake is washed with benzene and the filtrate is evaporated. The solid residue is boiled in methanol. After cooling, the product is filtered off and dried, yielding 19 parts (68%) of N-(2-acetylphenyl)-2,2,2-trichloroacetamide; mp. 112.7° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](OCC3CCN(C)CC3)=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:35][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:30]=2)[NH:25]1
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: CC1=CC(C)(C)Nc2ccc(Oc3ncnc4ccccc34)cc21
Yield: 110.3 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-74(1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (140 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[N:25]1[N:29]2[CH2:30][CH2:31][CH2:32][NH:33][C:28]2=[CH:27][CH:26]=1>>[N:25]1[N:29]2[CH2:30][CH2:31][CH2:32][N:33]([C:19]([C:18]3[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[CH:23][CH:22]=3)=[O:21])[C:28]2=[CH:27][CH:26]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: c1cc2n(n1)CCCN2
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCn3nccc32)cn1
Yield: 31 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4,5,6,7-tetrahydropyrazolo(1,5-a)-pyrimidine hydrochloride instead of methylamine, to the title compound (41 mg, 31%) which was obtained as a light yellow solid after crystallisation from ethyl acetate:hexane. MS: m/e=416.4 [M+H]′.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzyl chloroformate. Yield: 64% of theory, C35H35N7O5 (633.6) Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1) ##EQU131##
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[C:32]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=1)=[O:23])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol) were dissolved in tetrahydrofuran (6 mL). Acetyl chloride (234 mg, 3.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (1.06 g, 83.0%) as a white solid.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:19]=[C:20]2[C:26](=[CH:27][CH:28]=1)[CH:25]1O[CH:21]2[CH2:22][NH:23][CH2:24]1)([O-:17])=[O:16].C(=O)C.ClC(Cl)C>C(O)(=O)C>[CH2:22]([N:23]1[CH2:12][CH:11]2[O:13][CH:25]([C:26]3[C:20]2=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:28][CH:27]=3)[CH2:24]1)[CH3:21]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Agent: CC=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
Sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added to a solution of 4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (200 mg, 0.97 mmol), acetaldehyde (0.15 mL, 2.5 mmol), acetic acid (0.1 mL) and dichloroethane (5 mL). The reaction was stirred at room temperature for 5 h. The reaction was then quenched with saturated aqueous NaHCO3 (10 mL), extracted with CH2Cl2 (2×10 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (10-100% EtOAc in hexanes) to give 10-Ethyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a yellow oil (115 mg, 51%). MS (m/e) 235 (M+1).