Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](C(OC)=O)=[CH:7][C:5]=2[N:6]=1.[C:15]([O:18][CH2:19]C)(=[O:17])C>>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:15]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2sc(N)nc2c1
Reactant: CCOC(C)=O
Product: COC(=O)c1cccc2nc(N)sc12
Temperature: 30 °C

Procedure:
8.4 g of methyl 3-thioureido-benzoate are suspended in 120 ml of chlorobenzene, 2.2 ml of bromine in 30 ml of chlorobenzene are added at 0° C. in the course of 1 hour, while stirring as thoroughly as possible, and the mixture is then stirred to room temperature. It is then kept at 70° C. for 4 hours and subsequently cooled, a little diethyl ether is added and the precipitate is filtered off, mixed thoroughly with 70 ml of aqueous sodium bicarbonate solution, filtered off again and washed with water. 7.7 g (88%) of crude product of melting point 231°-232° C. result. HPLC analysis shows a content of more than 83% of the pure title compound, in addition to 8-18% of isomeric methyl 2-amino-benzothiazole-5-carboxylate. Suspension in and brief heating at 70° C. with ethyl acetate, cooling to 30° C. and filtration give the pure title compound of melting point >250° C. If the reaction is carried out in acetic acid (instead of in chlorobenzene), the content of the undesired isomeric methyl 2-amino-benzothiazole-5-carboxylate is only about 5%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.[CH3:28][N:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][N:31]=[CH:30]1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:34]([C:33]3[N:29]([CH3:28])[CH:30]=[N:31][CH:32]=3)=[O:35])[CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: Cn1cncc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cncc1C(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.04 g, 0.114 mmol), 3-Methyl-3H-imidazole-4-carbonyl chloride (0.083 g, 0.457 mmol) and triethylamine (138 mg, 1.37 mmol) in CH2Cl2 was stirred at 25° C. for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 43 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8w).
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.[CH:10]1([NH:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:10]1([N:16]2[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NNC1CCCCC1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=NN(C2CCCCC2)C(=O)C1
Temperature: 120 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 14.5 ml (0.134 mol) of methyl acetoacetate and 20.2 g (0.134 mol) of cyclohexylhydrazine hydrochloride was stirred at 120° C. for 2 hours, and then cooled. The reaction mixture was neutralized with 30 ml of a 4M aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. Hexane was added to the residue, and precipitated crystals were collected by filtration to obtain 19.0 g (79%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[CH3:52])([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46](OC(=O)C)[O:45]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[CH3:52])([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:45]1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@](C)(OC(C)=O)[C@@]1(C)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a stirred solution of 6-chloropurine (about 0.87 g, 5.7 mmol) in acetonitrile (about 20 ml) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (about 1.7 ml, 11.4 mmol) and Trimethylsilyl trifluoromethanesulfonate (about 2.76 ml, 15.2 mmol) at about 0° C., stirred for about 15 minutes then ((2R,3S,4R)-3,5-diacetoxy-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 1.4 g, 3.8 mmol) dissolved in Acetonitrile (about 20 ml) was added and reaction continued stirring at about 65° C. for about 8 hours. Completion of reaction monitored by thin-layer chromatography and quenched with saturated sodium bicarbonate. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 20% ethyl acetate: hexane as eluent furnished title compounds Isomer A and B (0.7 g) as a colorless liquid. Yield: 57%;
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:8]=[N+:9]=[N-:10].[CH2:11]([C@H:18]([NH:25]C(=O)OC(C)(C)C)[C@@H:19](O)[CH2:20]CCC)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[N:8]([C@@H:19]([CH2:20][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@@H:18]([NH2:25])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=N
Reactant: Oc1ccccc1
Reactant: CCCC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H](COc1ccccc1)[C@@H](N)Cc1ccccc1

Procedure:
Prepared in a manner to similar to intermediate XXII. Step A employed DMF as solvent and 3 equiv of phenol as nucleophile. Steps B and C were substituted with Mitsunobu hydrazoic acid inversion (see Intermediate I step C): ES MS (M+H)=283.6.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6]N=CC=1.[CH:10]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:29][CH:30]([O:32]C(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:10][O:9][C:1](=[O:8])[CH2:2][C@@H:7]1[CH2:6][CH2:29][CH2:30][O:32]1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: O=C(O)c1ccncc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1CCCO1
Reaction time: 0.5 h

Procedure:
A mixture of isonicotinic acid (114.4 g, 0.93 mol), PPh3 (333.2 g, 1.27 mol) and alcohol 3c (110 g, 0.85 mol), in THF (1.1 L) is treated with DIAD (249.5 mL, 1.3 mol) dropwise at 0° C. After stirring for 30 min, the cooling bath is removed and the mixture is stirred at RT for 2 h. The mixture is filtered and then concentrated. The residue is triturated with Et2O and the ether layers are extracted with 30% HCl. The combined aqueous phases are washed with Et2O (2×) and EtOAc (2×) and then neutralized with Na2HPO4 to about pH 6. The neutralized aqueous phase is extracted with Et2O (5×) and then DCM (3×). The combined ether layers are dried (MgSO4) and concentrated in vacuo. The DCM layers are combined and dried (MgSO4), concentrated in vacuo and combined with the product resulting from the ether extractions to afford ester 3d.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:33]([O-:36])(=[O:35])[CH3:34].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[C:33]([O:36][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:35])[CH3:34]
Reactant: Cc1ccc(Br)c2ncccc12
Reactant: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 8-bromo-5-methylquinoline (5.4 g, 24.3 mmol), N-bromosuccinimide (5.2 g, 29.2 mmol), and 2,2′-azobis(2-methylpropionitrile) (AIBN) (0.40 g, 24.3 mmol) in carbon tetrachloride (80 mL) was heated at reflux for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered, using hexane for rinsing. The filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 mL), and then sodium acetate (4.6 g, 48.8 mmol) was added. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with a mixture of ethyl acetate and hexane (3:7). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the title product as a pale yellow solid (4.8 g).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH:5]1[O:6][CH:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12.[NH2:14][CH:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[CH3:16].O>C1C=CC=CC=1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:15]([NH:14][CH2:3][CH:1]([C:7]2[O:6][C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:8]=2)[OH:2])[CH3:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(CC(C)N)cc1
Reactant: c1ccc2cocc2c1
Reactant: O=CC=O
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(CC(C)NCC(O)c2cc3ccccc3o2)cc1
Yield: 76.4 %

Procedure:
A mixture of 2-benzofuran glyoxal (10.44 g) and 2-amino-3-(4-methylphenyl)propane (8.94 g) was refluxed in benzene using a Dean and Stark head until the theoretical amount of water had been removed. The solvent was evaporated, replaced with methanol and sodium borohydride (5 g) added. The methanol was evaporated, the residue partitioned between water and ether and the ether layer dried. Filtration and evaporation gave an oil which was chromatographed on Kieselgel 60. Elution with 2% methanol-chloroform gave N-[2-(4-methylphenyl)-1-methylethyl]-2-(2-benzofuranyl)-2-hydroxyethanamine (14 g).
Reaction SMILES: N1CCC(C2C=CC3OCCC4N(N=C(C5N(CC(F)(F)F)N=CN=5)C=4)C=3C=2)CC1.C(OC([N:38]1[CH2:43][CH:42]=[C:41]([C:44]2[CH:45]=[CH:46][C:47]3[O:56][CH2:55][CH2:54][C:53]4[C:49](=[N:50][N:51]([C:57]5[N:58]([C:62]6[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=6[Cl:68])[N:59]=[CH:60][N:61]=5)[CH:52]=4)[C:48]=3[CH:69]=2)[CH2:40][CH2:39]1)=O)(C)(C)C>>[Cl:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[N:58]1[C:57]([N:51]2[N:50]=[C:49]3[C:53]([CH2:54][CH2:55][O:56][C:47]4[CH:46]=[CH:45][C:44]([CH:41]5[CH2:42][CH2:43][NH:38][CH2:39][CH2:40]5)=[CH:69][C:48]=43)=[CH:52]2)=[N:61][CH:60]=[N:59]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccccc4Cl)cc2CCO3)CC1
Agent: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Product: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(C3CCNCC3)ccc1OCC2

Procedure:
2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene from 4-{2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (490 mg, 0.9 mmol). The crude salt was partitioned between DCM and saturated aqueous sodium hydrogen carbonate, then the aqueous layer was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to reverse phase HPLC (Gemini C18 column, gradient MeOH in H2O+0.1% HCO2H) to give 154 (80 mg, 18%) as the mono formate salt. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H); 8.39 (s, 1H); 8.27 (s, 1H); 7.81-7.68 (m, 3H); 7.64 (td, J=7.60, 1.51 Hz, 1H); 7.09-7.03 (m, 2H); 6.90 (d, J=8.28 Hz, 1H); 4.19 (t, J=5.06 Hz, 2H); 3.32 (d, J=12.42 Hz, 2H); 3.04 (t, J=5.01 Hz, 2H); 2.89 (dd, J=13.45, 11.09 Hz, 2H); 2.54-2.56 (m, 1H); 1.69 (d, J=13.20 Hz, 2H); 1.58-1.45 (m, 2H). LCMS: RT=7.99 min, M+H+=447
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[S:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[S:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)cs2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)cs2)cc1
Reaction time: 0.25 h

Procedure:
182 mg (7.00 mmol) 95% Sodium hydride were given to a solution of 1.50 g (7.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 7.0 ml DMF and stirred for 15 min. 2.06 g (7.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-thiazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, then with n-heptane and finally a little amount of diethyl ether and dried at 45° C. in vacuum. Yield 2.4 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:22])(=[O:21])[NH:19][CH3:20])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1.B([O-])([O-])O[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].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.C1(C)C=CC=CC=1>[CH2:40]([O:39][CH2:38][CH2:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:22])[NH:19][CH3:20])=[CH:14][CH:13]=4)[CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=3[CH:27]=2)=[CH:35][CH:34]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CNS(=O)(=O)c1ccc(N2CCC(C(=O)OC)=Cc3cc(Br)ccc32)cc1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])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: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)NC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of methyl 7-bromo-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1 g), 4-(2-butoxyethoxy)phenyl borate (0.69 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (100 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.13 g), and the mixture was refluxed under argon atmosphere for 2.5 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1 g) as colorless crystals.
Reaction SMILES: C(OC([C:6]1([Br:14])[O:13][C:12]2[CH:11]=[CH:10][NH:9][C:8]=2[CH2:7]1)=O)C.[OH-:15].[Na+].[CH2:17]([OH:19])C>>[Br:14][C:6]1[O:13][C:12]2[CH:11]=[C:10]([C:17]([OH:19])=[O:15])[NH:9][C:8]=2[CH:7]=1
Reactant: CCOC(=O)C1(Br)Cc2[nH]ccc2O1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)c1cc2oc(Br)cc2[nH]1

Procedure:
2-Bromo-4H-furo[3,2-b]pyrrole-carboxylic acid ethyl ester (Krutosikova, A.; Kovac, J.; Dandarova, M.; Lesko, J.; Ferik, S., Collect Czech. Chem. Commun., 46: 2564-2573 (1981)) was hydrolyzed according to Procedure E (4 equiv 2 N NaOH, ethanol; reflux 5h, room temperature overnight; after concentration to remove ethanol, residue partitioned between ethyl acetate and 2 N HCl; combined organic phases dried over Na2SO4; no purification). 1H NMR (DMSO-d6) δ 12.47 (br s, 1H), 11.67 (s, 1H), 6.76 (d, J=0.8 Hz, 1H), 6.67 (t, J=0.8Hz, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11]1)(=O)[CH3:8].C(O)C>C1COCC1>[CH2:7]([N:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CC[C@H](CN)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN1CC[C@H](CN)C1
Yield: 66.5 %

Procedure:
Lithium aluminium hydride was added to a stirred solution of ((R)-1-acetylpyrrolidin-3-ylmethyl)amine (Intermediate 164, 1.5 g) in THF (50 mL) and the resulting mixture was stirred and heated at reflux for 2 hours. After cooling, ethanol was slowly added and the mixture was concentrated under vacuum. The residue was diluted with DCM and the solid was filtered off. The filtrate was evaporated to dryness to give ((R)-1-ethylpyrrolidin-3-ylmethyl)amine (0.9 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.O>[CH2:20]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.5 %

Procedure:
2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5 g, 20 mmol) was dissolved in N,N-dimethylformamide (60 ml), and potassium carbonate (5.4 g, 40 mmol) was added, followed by benzyl bromide (3.5 ml, 30 mmol), and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150 ml) and extracted into ethyl acetate (3×60 ml). The combined organic fractions were washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated in vacuo. Purification on silica, eluting with 2% and 5% ethyl acetate in hexane gave the title compound as a clear oil (6.7 g, 96%). 1H NMR (250 MHz, CDCl3) δ 5.47 (2H, s), 7.23 (1H, d, J=9 Hz), 7.43 (1H, dd J=8.2, 2.9 Hz), and 7.75 (6H, m).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([SH:15])[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]C.[C:22](O)(=O)C>[Fe]>[NH2:12][C:11]1[C:6]([NH:5][CH:1]([CH2:2][CH3:3])[CH3:22])=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([CH3:16])=[N:9][C:10]=1[SH:15]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(S)c1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC

Procedure:
6.2 g. of 4-sec. butylamino-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester are dissolved in 50 ml. of acetic acid. Iron dust is added carefully at relufx temperature until the mixture is colorless. The excess iron is filtered off and the filtrate is evaporated to dryness. The oily residue is dissolved in 10 ml. of methanol and precipitated by the addition of aqueous ammonia to obtain 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester, yield 3 g. (53%), m. p. 88°-89° (ethyl acetate).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26]Br>>[CH3:32][O:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1cc(CBr)cc(OC)c1
Product: COc1cc(Cn2c(Sc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)cc(OC)c1
Yield: 53.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (234 mg, yield: 53.1%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7]O)[CH:2]=[CH2:3].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][N:29]=[N+:30]=[N-:31])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(OC)cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CCOc1ccc(OC)cc1CN=[N+]=[N-]
Yield: 86 %

Procedure:
Step AS (3). To a solution of 2-allyloxy-5-methoxybenzyl alcohol (5 g, 26 mmol) in 75 mL of anhydrous THF was added diphenylphosphoryl azide (6 mL, 28.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (4.6 mL, 31 mmol) at 0° C. The mixture was refluxed for 1 h. The reaction was concentrated and the residue purified by silica gel chromatography eluting with 25% EtOAc in hexane to yield 2-allyloxy-5-methoxybenzyl azide as a colorless oil (4.9 g, 87%). (M−N3)+=177; 1H NMR (400 MHz, CDCl3) δ ppm 3.76 (s, 3H) 4.36 (s, 2H) 4.47-4.57 (m, 2H) 5.21-5.31 (m, 1H) 5.31-5.46 (m, 1H) 5.95-6.14 (m, 1H) 6.79-6.82 (m, 2H) 6.83-6.85 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CS(O)(=O)=O.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:23]3[CH:24]=[CH:25][C:20]([OH:26])=[CH:21][CH:22]=3)([C:23]3[CH:24]=[CH:25][C:20]([OH:26])=[CH:21][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: Oc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Product: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccc(Br)cc32)cc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 68.5 %

Procedure:
10 g of 2-bromofluorene, 2 equivalents of methane sulfonic acid and 100 g of phenol were placed into a 500 ml round-bottom flask, followed by stirring at 150° C. for 24 hours. The reaction solution was cooled and then mixed with water to filter solids. The solids were then recrystallized in toluene, to yield 12 g of (2-bromo-9,9-di(4-hydroxyphenyl)fluorene) (5).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][CH:24]=1.O.C(O)(=O)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:34]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(C2CNCCN2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(F)cc5)C4)cc3nc21
Temperature: 115 °C
Yield: 46.8 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.6 g) and (RS)-2-(4-fluorophenyl)piperazine (3.7 g) in pyridine (16 cc) is heated to a temperature in the region of 115° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 60° C. The residue is taken up with ethanol (40 cc) and concentrated again under reduced pressure under the above conditions. The solid obtained is taken up with water (10 cc), treated with 10% strength acetic acid (1.75 cc), drained and washed with water (2×10 cc) and ethanol (2×10 cc). After 2 recrystallizations in dimethylformamide (10 cc each time), (RS)-7-fluoro-8-[3-(4-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b ][1,8]naphthyridine-3-carboxylic acid (1.1 g) is obtained in the form of a yellow solid, m.p. 270°-275° C.