Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]([C:32]2([C:35](=[O:44])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:34][CH2:33]2)=[O:31])[C:26]([F:45])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:13])[CH:6]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH:16]1[CH2:17][CH:14]([C:12]([NH:11][C:7]2[CH:6]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:28][C:27]([NH:29][C:30]([C:32]4([C:35]([NH:36][C:37]5[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=5)=[O:44])[CH2:34][CH2:33]4)=[O:31])=[C:26]([F:45])[CH:25]=3)[CH:10]=[CH:9][N:8]=2)=[O:13])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)C1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate (220 mg, 0.35 mmol) in CH2Cl2 (4 mL) was added TFA (0.2 mL) at 0° C. and the reaction was stirred at room temperature overnight. Saturated NaHCO3 solution was added drop wise until pH>7 and the mixture with extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC separation to give N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (16 mg, yield 8.7%). 1H-NMR (400 MHz, MeOH-d4): δ 9.50 (s), 8.46 (d, J=7.2 Hz, 1H), 8.33 (dd, J=7.2 Hz, 12.4 Hz, 1H), 7.53-7.43 (m, 3H), 7.26 (dd, J=7.2 Hz, 2.4 Hz, 1H), 7.10 (t, J=8.4 Hz, 2H), 6.75 (d, J=2.4 Hz, 1H), 4.61-4.54 (m, 1H), 3.63-3.58 (m, 1H), 3.49-3.44 (m, 1H), 3.31-3.29 (m, 1H), 3.27-3.25 (m, 1H), 1.75-1.73 (m, 4H); MS (ESI): m/z 443.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24](=[O:35])[N:25]([C:28]1[S:32][C:31](Br)=[N:30][C:29]=1[Cl:34])[CH2:26][CH3:27])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C(OCC)(=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>[C:19]([O:23][C:24](=[O:35])[N:25]([C:28]1[S:32][C:31]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:30][C:29]=1[Cl:34])[CH2:26][CH3:27])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCN(C(=O)OC(C)(C)C)c1sc(Br)nc1Cl
Reactant: OB(O)c1cccnc1
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: CCOC(C)=O
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To a suspension of 3-pyridine boronic acid (1.5 g, 12.2 mmol) in toluene (50 mL) was added absolute ethanol (25 mL) followed by a 2.0 M solution of K2CO3 (12.5 mL). To this mixture was added (2-bromo-4-chloro-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester (4.2 g, 12.2 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (708 mg, 0.61 mmol). The reaction mixture was heated to 100° C. for 16 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The organic layer was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a red oil (3.3 g, 79%): 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 8.19 (dd, J=5.9, 4.2 Hz, 1H), 7.39 (dd, J=7.6, 5.2 Hz, 1H), 3.68 (q, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.22 (t, J=7.0 Hz, 3H); ESIMS m/z 340 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[ClH:22].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Reactant: Clc1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c(N3CCN(CCc4ccc(Cl)cc4)CC3)cccc2s1
Yield: 16.1 %

Procedure:
In an analogous manner to example 6, the title compound (0.56 g) as a white solid, mp 263°-266° C. dec. is prepared from ethyl-4-(1-piperazinyl)benzo[b]thiophene-2-carboxylate monohydrochloride (4.63 g, 14.2 mmol, prepared in example 5), 4-chlorophenethyl bromide (3.27 g, 14.9 mmol), sodium bicarbonate (2.44 g, 29.1 mmol) and anhydrous dimethyl sulfoxide (75 mL). The title compound is recrystallized from methanol (35 mL) and acetonitrile (35 mL); 1H NMR (DMSO-d6) δ 10.76 (1H, s), 8.10 (1H, s), 7.77 (1H, d, J=8.0 Hz), 7.44 (5H, m), 7.08 (1H, d, J=7.8 Hz), 4.37 (2H, q, J=7.0 Hz), 3.64 (4H, m), 3.56 (8H, m), 3.13 (2H, m), 1.34 (3 H, t, J=7.1 Hz); 13C NMR (DMSO-d6) δ 162.42, 151.71, 143.15, 132.82, 130.94, 128.95, 128.86, 128.63, 128.34, 117.59, 113.66, 113.59, 61.97, 52.66, 51.40, 31.20, 24.06, 14.47; IR (KBr) 1714, 1448, 1282, 1246, 754 cm-1 ; CI/MS (CH4) 429(100%). IC50 =53 nM (5HT1ABinding Affinity) IC50 =411 nM (5HT1DBinding Affinity) pA2 =6.51 (blocking of 5-HTl-like-mediated contraction in canine saphenous vein)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccncc2F)c2ccccc21
Product: COc1ccc(F)c(-c2cccc(C3(c4ccncc4F)N=C(N)c4ccccc43)c2)c1
Yield: 73 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine (Scheme #12, I) as described in Example 67 (Scheme #10, D) in 73% yield using 2-fluoro-5-methoxyphenylboronic acid. 1H NMR (DMSO-d6) δ 8.45 (d, J=2.78 Hz, 1 H), 8.34 (d, J=4.80 Hz, 1 H), 7.88-7.82 (m, 1 H), 7.77-7.69 (m, 1 H), 7.54-7.46 (m, 2 H), 7.45-7.30 (m, 4 H), 7.27-7.15 (m, 2 H), 7.04-6.85 (m, 4 H), 3.76 (s, 3 H); MS (ESI) m/z 428 [M+1]+.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O.C(N(C(C)C)CC)(C)C.[CH3:29][O:30][C:31](=[O:54])[C@H:32]([CH2:41][C:42]1[N:46]=[CH:45][N:44](C(OC(C)(C)C)=O)[CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:29][O:30][C:31](=[O:54])[C@H:32]([CH2:41][C:42]1[N:46]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[CH:45]=[N:44][CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: COc1ccccc1CO
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cncn1Cc1ccccc1OC)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 8 g methanesulfonic anhydride in 45 mL dichloromethane is chilled to -50° C. and treated dropwise with a solution of 6.2 mL 2-methoxybenzyl alcohol, 8.0 mL diisopropylethylamine and 45 mL dichloromethane. The resulting solution is warmed to 0° C. over 30 min and treated dropwise with 15.0 g N,1-bis-BOC-histidine methyl ester dissolved in 45 mL dichloromethane. The mixture is then heated at reflux 24 hr, poured into 400 mL 0.25M, pH=7 potassium phosphate buffer and the organic layer is separated, dried and evaporated. Chromatography on silica gel, eluting with chloroform-methanol (99:1) gives 3-(2-methoxyphenyl)methyl-N-BOC-histidine methyl ester as a gum. NMR (CDCl3) 4.96 (s,2H,NCH2Ar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=1[F:39]>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=1[F:39])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(OCC(F)(F)C(F)(F)F)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC(F)(F)C(F)(F)F)cc1F)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[(4-chloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 8) and 1-bromo-2-fluoro-4-(2,2,3,3,3-pentafluoro-propoxy)-benzene (Intermediate 34) in analogy to Example 1a): MS (ISN): 510.3 (M−H)−.
Reaction SMILES: [CH:1]1CCCCC=1.[CH2:7]1[CH:11]2[CH:12]3[CH:16]=[CH:15][CH:14]([CH:10]2[CH:9]=[CH:8]1)[CH2:13]3>C(Cl)(Cl)Cl>[CH:12]12[CH2:13][CH:14]([CH:15]=[CH:16]1)[CH:10]1[CH:11]2[CH2:7][CH2:1][CH2:8][CH2:9]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C1=CCCCC1
Solvent: ClC(Cl)Cl
Product: C1=CC2CC1C1CCCCC21
Reaction time: 5 h

Procedure:
82 g. (1 mole) of cyclohexene and 66 g. (0.5 mole) of dicyclopentadiene are reacted according to the batch procedure in 300 g. of chloroform. The reaction is carried out for 5 hours at 220° C. to produce a moderate yield of tricyclo [6.2.1.02,7 ] undec-9-ene.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([S@:23]([NH2:25])=[O:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14](/[CH:17]=[N:25]/[S@@:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (trans-4-(2-(benzyloxy)ethyl)cyclohexanecarbaldehyde (6.45 g, 26.18 mmol) and (R)-(+)-tert-butylsulfinamide (3.49 g, 28.8 mmol) in THF (66 mL) was added titanium(IV) ethoxide (8.78 mL, 41.89 mmol) under N2. The resulting solution was stirred at rt for 20 h and quenched by addition of saturated NaHCO3 solution dropwise. The mixture was vigorously stirred for 30 min and filtered through a pad of Celite, concentration. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the titled product (8.38 g, 92%). LC/MC: 350.1 (MH)+.
Reaction SMILES: ClCCl.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-:12].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:15]([O:12][C:17]1[C:16]2[C:18]([C:19]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:20]3[C:18]=1[CH:19]=[CH:20][CH:21]=[CH:22]3)=[CH:17][CH:16]=[CH:15][CH:15]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: [OH-]
Reactant: CCCCCCCCI
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCOc1c2ccccc2c(OCCCCCCCC)c2ccccc12
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To nitrogen saturated water (100 ml) and dichloromethane (100 ml) 9,10-anthraquinone (2.02 g, 9.61 mmol), sodium dithionite (3.39 g, 19.5 mmol), and Adogen 464 (3.5 g) was added. This was stirred for 5 minutes before addition of sodium hydroxide (3.8 g, 95.0 mmol). The reaction mixture was stirred for an additional 10 min and when it turned deep red 1-iodooctane (11.5 g, 47.9 mmol) was added drop wise. The reaction was stirred at room temperature under nitrogen atmosphere over night. The phases were separated and the water phase was extracted two times with dichloromethane and then the combined organic phases were washed two times with water and evaporated to obtain oil with crystals. These were recrystallised in ethanol and removed as starting material. After two crops the ethanol solution was cooled and the ensuing yellow crystals was purified by column chromatography using dichloromethane as mobile phase to yield 9,10-dioctyloxyanthracene (1.3 g, 2.99 mmol) as a white solid. 1H NMR (CDCl3, δ): 0.91 (t, 6H), 1.2-1.45 (m, 16H), 1.64 (m, 4H), 2.04 (m, 4H), 4.16 (t, 4H), 7.46 (m, 4H), 8.28 (m, 4H) MS MALDI-TOF (m/z): 434.247
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1>N1C=CC=CC=1>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[N:2]([CH3:1])[C:3](=[S:6])[NH:4][N:5]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNC(=S)NN
Solvent: c1ccncc1
Product: Cn1c(-c2ccc(F)cc2)n[nH]c1=S
Temperature: 25 °C

Procedure:
To 4-methylthiosemicarbazid (4.24 g, 40.30 mmol) in pyridine (50 ml) was added dropwise 4-fluorobenzoyl chloride (4.9 ml, 40.00 mmol) and the resulting mixture was stirred at r.t. o.n. The pyridine was removed by evaporation and the residue was heated in aq. sat. NaHCO3 at reflux o.n. After cooling to r.t., the product was collected by filtration, washed with water and dried under vacuum to give 3.22 g (38%) which was used in the next step without further purification. 1H NMR: 3.9 (m, 3 H) 6.98 (t, 2 H) 7.92 (m, 2 H).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27](=[O:28])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccccc1Oc1ccccc1

Procedure:
Using the same method as in Example 1-(ii), 2-phenoxyaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-oxo-2-[(2-phenoxyphenyl)amino]ethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 72%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Na].Cl.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl>C(Cl)(Cl)Cl.O.C(O)C>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:29])=[O:30])=[CH:26][CH:27]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(Nc3ncnc4cc(Cl)ccc34)cc2)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
N-Methylpiperazine (1.0 g, 0.01 mole) was dissolved in chloroform (50 ml). Sodium carbonte (10 g) was dissolved in water (50 ml). The solutions were combined and cooled to 10° C. 4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (3.85 g, 0.01 mole) was added in portions to the vigorously stirred solution. Stirring was continued for one hour. The chloroform layer was separated, dried and evaporated. The resulting gummy solid was redissolved in chloroform and chromatographed on an alumina column. Elution with chloroform gave a first band which was discarded. The second band was obtained as a low melting solid, which was converted to the hydrochloride by dissolving in ethanol and adding ethereal hydrogen chloride to give the title compound as the sesquihydrochloride (650 mg) m.p. 237°-239° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=3)[C:3]1=2.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:36])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=3)[C:3]1=2
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3cccc(C)c3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(COc2cc([Se]C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)c1

Procedure:
In a similar manner to that of Example 1g, by reacting 650 mg (1.2 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(3-methylbenzyloxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 240 mg of sodium hydroxide. A yellow crystallized solid is obtained (m=600 mg; yield=94%; m.p. 225° C.).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]1[C:28]([CH:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[CH:33][CH:32]=2)[OH:30])=[CH:27][N:26]=[CH:25]1>C(Cl)Cl>[CH3:23][N:24]1[C:28]([C:29]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[CH:35][CH:36]=2)=[O:30])=[CH:27][N:26]=[CH:25]1
Reactant: Cn1cncc1C(O)c1ccc(OC2CCCCO2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc(OC2CCCCO2)cc1
Reaction time: 1 h
Yield: 23 %

Procedure:
Dess-Martin periodinane (21 g, 50 mmol) was added to a solution of 74.1 (14 g crude, ˜50 mmol) in DCM (200 mL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1:2 EtOAc/hexane) to provide compound 74.2 (3.3 g, 11.5 mmol). MS ESI (pos.) m/e: 287.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Solid methyl 3,5-dimethoxy-2-methylbenzoate (5.83 g, J. C. S. Perkin I, 1973, 2853.) was dissolved in methanol (80 ml). A solution of aqueous sodium hydroxide (10%, 80 ml) was added and the solution stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure to approximately half of the original volume before adding aqueous hydrochloric acid (200 ml). The white precipitate that formed was extracted with ethyl acetate (2×250 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give the sub-title compound as a colourless solid (5.41 g).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[CH:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:20]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21]
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C1CCCC1
Yield: 86.8 %

Procedure:
Using the method of Example 53, using 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6 mmol), cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) and triethyl amine (4.07 g, 40.3 mmol), overnight at RT giving the title compound (9.13 g, yield 87%). 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.11 (d, 1H, J=7.8 Hz), 7.24-7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96-2.87 (m, 1H), 1.74-1.45 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:24](O)=[O:25]>>[C:16]([C:3]1[C:2]([NH:1][CH:24]=[O:25])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=CO
Reactant: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1
Product: CCCCOc1cc(C(=O)O)cc(NC=O)c1C(=O)c1ccccc1

Procedure:
A solution of 5-amino-4-benzoyl-3-n-butoxybenzoic acid (1.0 g) and formic acid (10 ml) is stirred at room temperature for 24 hours. After cooling, the resulting precipitate is collected and washed with ice-cold formic acid followed by cold water. After drying and recrystallization from ethanol, 4-benzoyl-3-n-butoxy-5-formamidobenzoic acid is obtained with a melting point of 180°-183° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10]Br)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-:29]>>[Br:1][C:2]1[C:3]([CH2:10][F:29])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(Br)c(CBr)n1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Cc1cc(C)c(Br)c(CF)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(bromomethyl)-4,6-dimethylpyridine (1.00 g) and TBAF (17.9 mL, 1 M solution in THF) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 30%) to give the title compound (651 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C=O.Cl.[C:23](O)(=O)C>C1C=CC=CC=1.CO>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:23][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Yield: 89 %

Procedure:
A suspension of 6 mmoles (1.6 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 50 ml of absolute benzene is admixed with a suspension of 7 mmoles (0.02 g) of paraformaldehyde in 10 ml of absolute methanol. The reaction mixture is refluxed for two hours in the presence of a catalytic amount of hydrochloric acid or acetic acid, whereupon the obtained pale-yellow solution is evaporated in vacuo. The residual oily product is triturated with a small amount of acetone to yield the aimed compound in crystalline form in a yield of 89%.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([N+:24]([O-])=O)=[C:5]([O:22][CH3:23])[C:6]2[NH:10][C:9](=[O:11])[N:8]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:7]=2[C:20]=1[F:21].C(OCC)(=O)C>C1COCC1.CCCCCC.[Zn]>[NH2:24][C:4]1[C:3]([F:2])=[C:20]([F:21])[C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:9](=[O:11])[NH:10][C:6]=2[C:5]=1[O:22][CH3:23]
Reactant: COc1c([N+](=O)[O-])c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Agent: Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(N)c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
Concentrated HCl (2.5 mL) was added to a solution of 6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-methoxy-5-nitro-1,3-dihydro-benzoimidazol-2-one (1.6 g, 3.4 mmol) in THF (35 mL) and the resulting mixture was stirred for 5 min. This was followed by portion wise addition of zinc powder (2.2 g, 34 mmol) over a period of 30 minutes and stirring was continued for a further 30 minutes at room temperature. The reaction was monitored by TLC (60% ethyl acetate in hexane). The reaction mixture was concentrated and the concentrate was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product was triturated with ether, filtered and the residue was dried to afford 1.4 g of the product (94.5% yield).