Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([O:7][N:8]=[C:9]2[CH2:26][CH2:25][C:12]3([O:16][N:15]=[C:14]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4][O:3]1.[OH-:27].[Na+]>O1CCOCC1>[OH:27][CH2:4][CH2:5][CH:6]([O:7][N:8]=[C:9]1[CH2:26][CH2:25][C:12]2([O:16][N:15]=[C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[CH2:11][CH2:10]1)[C:2]([OH:3])=[O:1]
Reactant: O=C1OCCC1ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C(CCO)ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Temperature: 40 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a solution of the Compound of Example 47 (14 mg, 0.4 mmol) in 1.75 mL of dioxane was added 1M sodium hydroxide (40 μL, 0.4 mmol) and the reaction mixture was stirred at 40° C. for 2 h. After evaporation to dryness, the crude was purified by automated RP flash chromatography (SP1®TM-Biotage; gradient 20 mM aqueous ammonium carbonate-MeCN from 1:0 to 6:4) to give 10 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)[CH:50]=[CH:49][C:48]=1[NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.O>[C:61]([O:60][C:59](=[O:65])[NH:58][C:48]1[CH:49]=[CH:50][C:51]([C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)=[CH:52][C:47]=1[NH:46][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:17][CH:18]=1)([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Reactant: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-{1-[(Acetylamino)methyl]-2-anilino-2-oxoethyl}benzoic acid (232 mg, 0.71 mmol), EDCI (176 mg, 0.92 mmol), and HOBT (124 mg, 0.92 mmol) were combined in DMF (8 mL) and stirred for 10 minutes before adding tert-butyl [2-amino-4-(3-thienyl)phenyl]carbamate (227 mg, 0.78 mmol). The reaction was then stirred at 60° C. for 24 h. The solution was cooled to room temperature, poured into water (40 mL), and filtered to collect an orange solid. The crude solid was dissolved in CH2Cl2 (25 mL) and hexanes (20 mL), concentrated to half volume, and filtered to give tert-butyl[2-[(4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoyl)amino]-4-(3-thienyl)phenyl]carbamate as a white solid. MS (ESI) calcd [M+H]+ 599.2, found 599.1.
Reaction SMILES: C([O:3][C:4]1[C:13]2[CH:12]=[N:11][C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:9][C:8]=2[N:7]=[CH:6][C:5]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.CO[CH2:28][CH2:29]OC>>[CH2:28]([N:7]1[C:8]2[N:9]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:11]=[CH:12][C:13]=2[C:4](=[O:3])[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)[CH3:29]
Reactant: COCCOC
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C)CC3)ncc2c1=O

Procedure:
A mixture containing 1.0 g of ethyl 5-ethoxy-2-(4-methyl-1-piperazinyl)pyrido[ 2,3-d]pyrimidine-6-carboxylate and 5.0 ml of dimethylene glycol dimethyl ether was heated to reflux for 3 hours. The solvent was removed by distillation is vacuo and the residual solid was recrystallized from water to yield 0.72 g of the product, m.p. 146° - 147°C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (2.6 g, 4.8 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (8 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (2.8 g, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][C:22]24[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]2)[CH2:29]4)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH2:21][C:22]24[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]2)[CH2:29]4)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC24CC5CC(CC(C5)C2)C4)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc3c2C=C(CC24CC5CC(CC(C5)C2)C4)C3)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
94.0 g (228 mmole) 7-(4′-tert-Butyl-phenyl)-2-(1-adamantylmethyl)-indan-1-one were dissolved in 291 ml toluene in a 1 l-roundbottom flask equipped with a reflux condenser. 9.5 g (1:1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 6 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 900 ml ethanol afforded 76.9 g (85%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.44, 7.32, 7.23, 7.12 (4×m, 7H, aromatic), 6.63 (s, 1H, ═CH), 3.32 (s, 2H, benzylic), 2.29 (d, 2H, aliphatic), 1.69-1.15 (m, 15H, aliphatic), 1.38 (s, 9H, C(CH3)3) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18].ClCCl>CO>[Cl:16][S:17]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:2]([CH3:15])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)(=[O:19])=[O:18]
Reactant: COC(=O)C(C)(C)COc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)(C)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
Methyl 2,2-dimethyl-3-phenoxypropionate (Intermediate A36, 36 g, 0.17 mol) was added dropwise over 60 min to rapidly stirred chlorosulfonic acid that was maintained at −5° C. The mixture was warmed to room temperature, stirred for an additional 90 min, and poured into a cooled, rapidly stirring mixture of dichloromethane (250 mL) and methanol (30 mL). The mixture was stirred for 30 min while being cooled and then for 60 min at room temperature. It was then washed with several portions of ice-water. The combined aqueous layers were extracted with a small portion of dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was stirred with hexanes and collected by filtration to yield 19 g (36%) of the title compound, sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:4][C:5]([CH2:7][N:8]1[CH2:11][CH2:10][C:9]1=[O:12])=[O:6])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C[Si](C)(C)Cl.P(Cl)(OC1C=CC=CC=1)(O[C:31]1[CH:36]=CC=C[CH:32]=1)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>O1CCCC1.CN(C)C=O>[CH2:1]([O:4][C:5]([C:7]1[N:8]2[C:9](=[O:12])[CH2:10][C@H:11]2[CH:31]([CH3:36])[CH:32]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CN1CCC1=O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=CC(C)[C@@H]2CC(=O)N12
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-{(1R)-1-]((4R)-pyrrolidine-2-thion-4-ylthio)carbonyl]-ethyl}-1-(allyloxycarbonylmethyl)-2-azetidinone (1.028 g) in tetrahydrofuran (6 ml) is added dropwise to 1M solution (6.6 ml) of sodium bis(trimethylsilyl)amide in tetrahydrofuran at -60° C. to -50° C. over a period of 5 minutes. The mixture is stirred at -50° C. for 10 minutes, and thereto is added trimethylchlorosilane (0.58 ml) at -60° C. The mixture is stirred at the same temperature for 15 minutes, and thereto is added diphenyl chlorophosphate (0.44 ml) at -60° C. The mixture is stirred at 0° C. for 1.5 hour, and to the reaction mixture is added dimethylformamide (10 ml) at 0° C., and further thereto is added dropwise 1M solution (1.6 ml) of tetra-n-butylammonium fluoride in tetrahydrofuran at -60° C. The mixture is stirred at -50° C. for 30 minutes, and warmed to -20° C. over a period of one hour. After the reaction is complete, the reaction solution is poured into a phosphate buffer (pH 7.0, 20 ml), and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the ethyl acetate layers are combined, washed twice with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane:chloroform:ethyl acetate=5:5:4) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-](1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (575 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([CH3:19])=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([CH3:19])=[C:10]([N:12]([CH2:21][CH3:22])[CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC=O
Reactant: COC(=O)c1c(C)c(NC2CCOCC2)cc(Br)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCN(c1cc(Br)c(F)c(C(=O)OC)c1C)C1CCOCC1
Yield: 96.3 %

Procedure:
To a solution of methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate (500 mg, 1.44 mmol) in 1,2-Dichloroethane (15 ml) at room temperature and under nitrogen was added acetaldehyde (0.81 ml, 14.44 mmol) followed by acetic acid (0.5 ml, 8.67 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3.06 g, 14.44 mmol) at room temperature. After stirring for 2 hours deionized water (20 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 519 mg (96%) of methyl 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoate as a pale yellow oil that solidified upon standing. LC-MS 94%, 2.45 min (3 minute LC-MS method), m/z=373.9/375.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.33 (d, J=6.6 Hz, 1H), 3.95 (s, 5H), 3.32 (td, J=11.7, 2.1 Hz, 2H), 3.00 (q, J=7.1 Hz, 2H), 2.88 (tt, J=10.9, 4.0 Hz, 1H), 2.25 (s, 3H), 1.73-1.54 (m, 4H), 0.85 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:52])[C:35]([CH3:51])([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:51][C:35]([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:52])=[O:33]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 24 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.132 mmol) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (see Ex. 1, Part C) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce the product as a white solid (24%). MS [EI+] 540 (M+H)+, 562 (M+Na)+, [EI−] 538 (M−H)+; HPLC: T=3.24 min, purity 100%.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)C)C1C=CC=CC=1>O1CCCC1.[Pd]>[CH3:9][NH:10][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1
Reactant: CN(C[C@H]1CC[C@H](CCO)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC[C@H]1CC[C@H](CCO)CC1
Reaction time: 3 h

Procedure:
0.62 g (2.03 mmol) trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid benzyl ester dissolved in 10 ml of tetrahydrofuran were submitted to a hydrogenation over 0.3 g of 5% palladium on charcoal as catalyst, at normal pressure and ambient temperature. The cleavage of the benzyloxycarbonyl group was complete after 3 hours. After removal of the catalyst by filtration and evaporation of the solvent, 0.33 g (95%) of trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol were obtained as a colorless oil, MS: 172 (MH+).
Reaction SMILES: [NH:1]([CH:8]=[C:9]([N+:15]([O-])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](C(CC)(CC)C([O-])([O-])[O-])[CH3:19]>>[CH3:18][C:19]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:15]=1
Reactant: CCOC(=O)C(=CNc1ccccc1)[N+](=O)[O-]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(=O)c1cn(-c2ccccc2)c(C)n1

Procedure:
Part A: Ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate (4.8 gram, 21% yield) was prepared according to the procedure described (in J. Heterocyclic Chem. 1987, 24, 1757-1763) from ethyl 3-anilino-2-nitro-acrylate (23.6 gram, 0.01 mol) and triethylorthoacetate (150 ml). The initially formed crude product was purified by flash chromatography (eluent: diethyl ether). Rf (diethylether˜0.15) to give pure ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(OCC)(=O)C.CCCCCC>C1COCC1.C(OCC)(=O)C.C(OC(C)C)(C)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2
Reactant: Nc1cccc2ccc(O)cc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Nc1cccc2c1CC(O)CC2
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 8-amino-2-naphthol (40 g, 0.25 mol) in THF (800 ml, 20 times), Boc anhydride (54.8 g (57.7 ml), 0.25 mol, 1 eq) was added at rt. The overall reaction mass was heated to 70° C. and maintained for 24 hrs at the same temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.6). On completion of the reaction, solvent was distilled off completely and the residue obtained was taken in ethyl acetate (200 ml). Organic layer was washed with saturated sodium carbonate solution (2×200 ml) followed by with water (2×200 ml), dried the contents over sodium sulfate and concentrated under reduced pressure. The crude obtained was taken in diisopropyl ether (150 ml), stirred for 15 min and filtered. Solid obtained was washed with diisopropyl ether again and dried to yield the required product as an off white solid (49 g, 75% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:15]([S:12]([NH:11][CH3:10])(=[O:13])=[O:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: CNS(=O)(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1-c1ccc(Br)c(F)c1
Reaction time: 0.17 h

Procedure:
1-Bromo-2-fluoro-4-iodobenzene (6.30 g, 20.9 mmol) and (2-(N-methyl-sulfamoyl)-phenyl)boronic acid (4.50 g, 20.9 mmol) were added to a 250 mL flask equipped with a stir bar and reflux condenser. 1,4-Dioxane (50 mL) and Na2CO3 (2 M, 50 mL) were added. Argon was bubbled through the solvent while it was rapidly stirred for 10 minutes before Pd(dppf)Cl2.CH2Cl2 (766 mg, 1.05 mmol) was added and the reaction was stirred at 80° Celsius for 15 hours. The reaction was then diluted with 50 mL of water and extracted with ethyl acetate (1×50 mL, 3×100 mL). The combined organic extracts were dried with Na2CO3, filtered and concentrated to dryness. The crude product was purified by FCC to give 4′-bromo-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide. 1H NMR (500 MHz, CDCl3) δ 8.17-8.11 (m, 1H), 7.66-7.59 (m, 2H), 7.59-7.54 (m, 1H), 7.33-7.29 (m, 1H), 7.28-7.23 (m, 1H), 7.20-7.13 (m, 1H), 3.67-3.56 (dd, J=10.1, 4.5, 1H), 2.46-2.43 (d, J=5.3, 3H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH2:19]([OH:22])[CH2:20][CH3:21]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH2:19][CH2:20][CH3:21])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCCO
Agent: [Na]
Product: CCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium propylate in n-propanol there is obtained propyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 147° C. (with decomposition);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nn(CCN3CCCC3)cc2C1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.8 g, 8.06 mmol)(EP1057814, Example 2c) was added to 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.65 g, 9.67 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in N,N-dimethylformamide (35 ml) and the mixture was heated at 65° C. for 26 hours, then cooled to room temperature and stirred for 72 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in 2N sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate (×2) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ammonium hydroxide, methanol and ethyl acetate in dichloromethane as eluant (gradient from 0:0:50:50 to 0:0.1:50:50 to 0.5:5:0:95) to give the title compounds from preparation 228-A and preparation 228-B as a mixture of isomers (300 mg). LRMS: m/z ES+ 321 [MH+]
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[K+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O.Cl[Si](C)(C)C.C1CCN2C(=NCCC2)CC1.C1N=CN(C(N2C=NC=C2)=O)C=1>CC#N.CCOC(C)=O.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](=[O:6])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-5-iodobenzoic acid (4.03 g, 15.14 mmol) in 11 mL freshly distilled THF is added CDl (2.96 g, 18.24 mmol) in small portions. Vigorous gas evolution is observed. The reaction is stirred overnight. In a separate flask, ethyl malonate potassium salt (2.84 g, 16.69 mmol) is suspended in 10 mL CH3CN. To this solution is added chlorotrimethylsilane (2.15 mL, 16.94 mmol) and the reaction is stirred at room temperature overnight. The latter reaction is cooled to 0° C. and DBU (5.00 mL, 33.43 mmol) is added dropwise. This reaction is stirred at 0° C. for 3 h. The solution of the CDI adduct is then cannulated over and the mixture is stirred at 0° C. for 2 h. Upon complete conversion to product as evidenced by TLC, the solution is quenched with water and 6N HCl (8 mL). The reaction is partitioned with diethyl ether. The organic layer is washed with 1N HCl and then brine, dried over Na2SO4, filtered, and concentrated to give a light orange oil. The oil is dissolved in EtOAc and adsorbed onto silica. Purification by chromatography (eluent 3% EtOAc/hexanes) affords the desired product as a colorless oil which crystallized upon standing (2.51 g, 7.46 mmol, 49%). Physical characteristics are as follows: m.p. 54-56° C.; 1H NMR (300 MHz, CDCl3) δ 12.67, 8.18, 7.70, 6.89, 5.54, 4.28, 1.35; IR (drift) 2984, 1627, 1558, 1476, 1422, 1390, 1358, 1292, 1262, 1221, 1201, 1071, 1028, 823, 807 cm −1; MS (EI) m/z 336 (M+), 336, 249, 122, 107, 94, 86, 84, 69, 68, 51; Anal. Calcd for C11H10FIO3: C, 39.31; H, 3.00; Found: C, 39.35; H, 2.92.