Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH2:12]([NH:19][CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[C:28]([OH:32])[C:29]([Cl:31])=[CH:30][C:22]=2[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[ClH:31].[CH2:12]([N:19]([CH2:2][C@H:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[C:28]([OH:32])[C:29]([Cl:31])=[CH:30][C:22]=2[CH2:21]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: Oc1cc2c(cc1Cl)CC(NCc1ccccc1)CCC2
Solvent: CCO
Product: Cl
Product: Oc1cc2c(cc1Cl)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Yield: 206.9 %

Procedure:
A solution of (2S)-1,2-epoxy-3-phenoxypropane (53 mg) (IL FARMACO, 50 (10), 643 (1995)) and N-benzyl -(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (89 mg) in ethanol (1 ml) was refluxed for 19 hours, cooled to room temperature and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) by silica gel (2.9 g), and the eluate was treated with 4N hydrogen chloride in ethyl acetate to afford (2S)-1-[N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl) amino]-3-phenoxy-2-propanol hydrochloride (149 mg) as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[CH:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][CH:29]=3)=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)C=C.O=O.C(NCC)C>ClCCl.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>[NH2:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[CH:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][CH:29]=3)=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: C=CCOC(=O)NC1(c2ccc(C(Nc3ccc(-c4cn(C)cn4)cc3)=C3C(=O)Oc4ccccc43)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=O
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(NC(=C3C(=O)Oc4ccccc43)c3ccc(C4(N)CC4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.58 g of allyl(1-{4-[[4-(1-methyl-1H-imidazol-4-yl)phenylamino]-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)carbamate was dissolved in 20 mL of dichloromethane. The solution was freed from oxygen using argon. Then at RT, 0.52 mL of diethylamine and 0.058 g of tetrakis(triphenylphosphine)palladium (0) were added. The mixture was stirred for 2 hours at RT, the suspension was evaporated down with silica gel and chromatographed with dichloromethane/methanol (97:3) on silica gel 70 at a flow rate of 30 mL/min. The clean fractions were combined, evaporated down to the residue, dissolved in dichloromethane, filtered, and combined with diisopropyl ether. The dichloromethane was distilled off, the crystals formed were suction filtered and washed with diisopropyl ether. Yield: 0.26 g of yellow crystals, melting point 190° C.-191° C., as base. Rf value: 0.51 (dichloromethane/methanol (9:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7]1[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH3:18])=[CH:16][C:9]=2[N:8]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7]1[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][C:15]([N:17]([CH3:18])[C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:29][C:30]4[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=4)[N:20]=3)=[CH:16][C:9]=2[N:8]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1cccc(Cl)c1)n2C)c1ccnc(Cl)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CN(c1ccc2c(c1)nc(NCc1cccc(Cl)c1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(3-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (50 mg, 0.12 mmol) and 3-amino-benzenesulfonamide (21 mg, 0.12 mmol) as a white solid (31 mg, 44%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.51 (s, 1H), 8.60 (s, 1H), 7.76-7.80 (M, 2H), 7.25-7.47 (m, 10H), 7.13 (s, 1H), 6.90 (d, J=7.8 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 3.61 (s, 3H), 3.45 (s, 3H). MS (ESI) m/z=549 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[Si:8](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1[CH:30]=[CH:29]N=C1.Cl>CN(C=O)C>[Si:8]([O:1][CH2:2][C:3](=[CH2:7])[C:4]([O:6][CH2:29][CH3:30])=[O:5])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C(CO)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: C=C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of 2-(hydroxymethyl)acrylic acid (520 mg) in DMF (5.0 mL) were added tert-butyldiphenylsilyl chloride (1.65 g) and imidazole (680 mg) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuum condition. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1→9:1) to give the title compound (1.35 g) having the following physical data.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)=[CH:13][CH:12]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:27]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of phenol (0.66 g, 7.08 mmol) in THF (5 mL) is added NaH (0.24 g, 5.91 mmol) followed by a solution of the crude 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 5, prepared herein above (0.25 g, 0.67 mmol) in THF (2 mL). The reaction mixture is stirred for 1.5 hours at room temperature, diluted with aqueous NaHCO3 and extracted with twice with ethyl acetate. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product which is purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to provide 0.35 g (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) □ 8.47 (d, J=5.1 Hz, 1H), 7.49 (dd, J=7.8, 7.8 Hz, 2H), 7.40 (ddd, J=5.4, 5.4 Hz, 2H),7.35-7.22 (m, 3H), 7.10 (dd, J=8.4, 8.4 Hz, 2H), 6.90 (d, J=6.8 Hz, 2H), 4.05 (t, J=7.2 Hz, 2H), 3.86 (t, J=7.2 Hz, 2H), 2.59 (dt, J=7.2, 7.2 Hz, 2H); HRMS cald for C22H18FN4O2(M+H)+ 389.1414; found 389.1407. This compound corresponds to analog 1 from Table I.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[C:5](OC)=[O:6]>O1CCCC1.C1C=CC=CC=1.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(C)ccc1Sc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccccc2)c(CO)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
322.5 g of methyl 3-methyl-6-(phenylthio)-benzoate in 3 litres of absolute tetrahydrofuran are treated dropwise over a period of 30 minutes under argon and under reflux with 420 ml of a 70% sodium-dihydro-bis(2-methoxyethoxy)-aluminate solution in benzene and the mixture is boiled for a further 3 hours under reflux. Then the mixture is cooled to ca 4° C, diluted with 1 litre of benzene, hydrolysed with 700 ml of 2-N hydrochloric acid, then poured on to ice-water and treated with a further 400 ml of concentrated hydrochloric acid in order to obtain a clear solution. The organic phase is washed with water, dried over sodium sulphate, filtered and evaporated. There is obtained 3-methyl-6-(phenylthio)-benzyl alcohol as a red-brown oil.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][CH2:13][CH:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:23](Cl)(Cl)=[O:24].C1(C)C=CC=CC=1.[C:34]1([CH2:40][O:41][C:42]([NH:44][C@H:45]2[CH2:48][NH:47][C:46]2=[O:49])=[O:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C1C=CC=CN=1)C>ClCCl>[C:34]1([CH2:40][O:41][C:42]([NH:44][CH:45]2[CH2:48][N:47]([C:46]([N:1]3[CH2:15][CH2:14][CH2:13][C@H:2]3[C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:4])=[O:49])[C:23]2=[O:24])=[O:43])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: O=C(OCc1ccccc1)C1CCCN1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1CN(C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)C1=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
A solution of d,l-proline, benzyl ester (1.13 grams, 5.5 mmol) in 6 ml of dichloromethane was cooled to 0° C. and 1.2 equivalents (0.92 ml) of triethylamine (668 mg, 6.6 mmol) was added. The resulting mixture was immediately added dropwise to a solution of 20% phosgene in toluene (6 ml, 9.9 mmol) at -25° C. After stirring at -25° C. for 1 hour, the volatiles were evaporated without external heating, and the residue was redissolved in 10 ml of dichloromethane and cooled to 0° C. (S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (1.21 grams, 5.5 mmol) and dimethylaminopyridine (67 mg, 0.55 mmol) were added to the stirring solution. Triethylamine (0.92 ml, 6.6 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was washed with water, dried over anhydrous Na2SO4, filtered and the dichloromethane removed in vacuo. The residue was purified by flash chromatography on silica gel 230-400 mesh (eluting with 40% ethyl acetate in hexane) yielding 1.2 grams of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:16]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24])(=[O:19])(=[O:18])[NH2:17]>COCCOC>[C:1]1([NH:7][NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([S:16](=[O:18])(=[O:19])[NH2:17])[CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: NNc1ccccc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reaction time: 144 h
Yield: 44.8 %

Procedure:
In a 1 liter round bottom flask were placed phenyl hydrazine (54.1 g, 0.5 mol), triethylamine (50.5 g, 0.5 mol), and 150 ml of 1,2 dimethoxyethane. Then the mixture was cooled to ice-bath temperature and with good stirring and over 10 minutes a solution of 3-sulfamoyl-4-chlorobenzoyl chloride 97.1% (61 g, 0.24 mol) in 150 ml 1,2 dimethoxyethane was added dropwise. The reaction was permitted to reach ambient temperature. After standing for 6 days the solvent was evaporated under vacuum and the residue taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 2N H2SO4, with water and finally with 1 molar sodium bicarbonate solution. The ethyl acetate phase was separated and dried with magnesium sulfate, clarified and concentrated to crystallization. 35 g of product mp 189°-190° C. were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[C@H:8]([CH2:19][CH2:18][C:17]2[CH:16]=[CH:21][C:25]([O:24][CH2:23][CH2:22][CH2:16][CH2:17][C:18]3[CH:14]=[CH:13][CH:5]=[CH:4][CH:19]=3)=[C:7]([O:10][CH3:11])[CH:8]=2)[N:9]=1)[CH3:2]
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Product: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1CCc1ccc(OCCCCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydro-pyrazine (2.2 g; 10.4 mmol; Lohr, Birgit et al., Synlett, 1999, 7, 1139-1141) in dry THF (30 ml) at −78° C. there is added n-butyllithium (6.5 ml; 10.4 mmol; 1.6M in n-hexane). After 30 minutes at −78° C. the endproduct of step b) (4.3 g; 10.4 mmol) dissolved in dry THF (15 ml) is added tropwise over a period of 10 minutes. The reaction mixture is allowed to warm up to RT and it is kept at RT for 20 hours. After quenching with saturated aqueous ammonium chloride solution and extraction (2 times) with ethyl acetate the organic phase is dried over MgSO4 and concentrated under reduced pressure. The crude is purified on silica gel using diethylether/n-hexane (1/9) as mobile phase.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:26])=[C:12]([O:14][CH:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[Cl:25])[CH3:16])[CH:13]=2)=[CH:4][CH:3]=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1CCCC1=O>[Cl:25][C:18]1[C:19]([F:24])=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH:15]([O:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:33][CH2:34]3)=[N:7][CH:6]=2)[CH:9]=[N:10][C:11]=1[NH2:26])[CH3:16]
Reactant: CC(Oc1cc(-c2ccc(Br)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN1CCCC1=O
Product: CC(Oc1cc(-c2ccc(N3CCC(N4CCCC4)CC3)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Yield: 50 %

Procedure:
A tube was charged with 6′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine (92 mg, 0.20 mmol), 4-pyrrolidin-1-yl-piperidine (0.62 g, 4.0 mmol) and N-methylpyrrolidinone (0.8 mL). The tube was sealed and the mixture was heated at 80° C. overnight. The temperature was increased to 100° C. for 5.5 hours and then heating was ceased. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol, ammonium hydroxide to afford 5″-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-4-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′;5′,3″]terpyridin-6″-ylamine (53 mg, 50%).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[C-:15]#[N:16].[Na+].[C:18](=[O:21])([O-])[O-:19].[NH4+].[NH4+]>C(O)C>[C:9]1([C:1]2[CH:2]=[CH:3][C:4]([NH:16][CH2:15][C:18]([OH:19])=[O:21])=[CH:5][CH:6]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: [C-]#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CNc1ccc(-c2ccccc2)cc1
Yield: 41.5 %

Procedure:
A solution of 4-biphenylcarboxaldehyde (4.6 g 25 mmol), sodium cyanide (3.68 g 75 mmol) and ammonium carbonate (9.60 g 100 mmol) in 50% aqueous ethanol (175 ml) was heated at 50° C. for 20 hours. The reaction mixture was cooled, concentrated under reduced pressure and acidified to pH 2.0 with concentrated hydrochloric acid (fume hood). The intermediate 4-(4-phenylphenyl)-2,5-imidazolinedione was collected by filtration, washed with dilute (0.5%) HCl and dried before using as crude in the next stage. (Filtrates were retained and treated with sodium hypochlorite solution before disposal) The intermediate 4-(4-phenylphenyl)-2,5-imidazolinedione was refluxed in 16% aqueous sodium hydroxide (100 ml, 16% w/v) for 24 h. The reaction mixture was then filtered, cooled, diluted with water (100 ml) and then shaken with ethyl acetate and separated. The aqueous solution was adjusted to pH 5.1 with concentrated hydrochloric acid and the solid obtained collected by filtration, washed with a little water and dried to give 4-phenylphenylglycine (2.36 g, 42%). 1H nmr (d6 DMSO) consistent with desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 32.6 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and piperidine (0.040 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (35 mg, 0.088 mmol, yield 33%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:24]1[CH2:23][CH2:22][N:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH2:26][CH2:25]1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Fc1ccccc1N1CCNCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2F)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Fluoro-5-nitro-benzoyl chloride and 1-(2-fluorophenyl)-piperazine (52%, orange solid, MS (m/e): 348.1 (M+H, 100%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:15]([CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:37])[CH3:36]
Reactant: COCOc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(OCOC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 79.1 %

Procedure:
The portion of 120 mg of 60% sodium hydride were suspended in 10 ml of dimethylformamide, and cooled to 0° C., followed by dropwise addition of 1.22 g of N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide, and then followed by addition of 326 mg of ethyl chlorocarbonate. After stirring at room temperature for 19 hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from the fraction eluted with methylene chloride was obtained 1.12 g of N-ethoxycarbonyl-N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)sc1C=O

Procedure:
26 g of 3-methyl-2-thiophenecarboxaldehyde was dissolved in 100 ml of chloroform and the solution was stirred by cooling with ice. 11 ml of bromine was added dropwise thereto. The temperature was elevated to room temperature and the mixture was stirred overnight. About 1 l of ethyl acetate was added thereto and the mixture was washed with water, then with a saturated aqueous sodium hydrogencarbonate solution and finally with a saturated aqueous common salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 46.8 g of 5-bromo-3-methyl-2-thiophenecarboxaldehyde in the form of a dark brown solid, which was subjected to the subsequent reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.[I:28]N1C(=O)CCC1=O>[Al].C1COCC1>[NH2:1][C:2]1[C:9]([I:28])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(I)c(N)cc1C(F)(F)F

Procedure:
4-Amino-2-trifluoromethyl-benzonitrile (20.44 g, 109.79 mmoles) and p-toluenesulfonic acid monohydrate (1.05 g, 5.52 mmoles) were dissolved methanol (200 mL) and THF (200 mL), and the reaction mixture was stirred under a nitrogen atmosphere. The reaction vessel was wrapped in aluminium foil, while the solution was stirred for 20 min., then N-iodosuccinimide (30.41 g, 135.17 mmoles) was added and the reaction was allowed to stir overnight (16 hrs). The reaction mixture was concentrated in vacuo, triturated with hexanes (3×400 mL) and concentrated to dryness. The crude solid was dissolved in diethyl ether (400 mL), washed with water (3×), the organic extracts were diluted with hexanes (400 mL) and a white solid precipitated. The solid was filtered and dried in a vacuum oven (35° C. @ 762 Torr) overnight to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C.O.C1C=CC=CC=1>[CH2:22]([O:21][C:19]([C:18](=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:16]#[N:17])=[O:20])[CH3:23]
Reactant: CCOC(=O)CC#N
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccc(C)cc1
Yield: 74.6 %

Procedure:
A mixture of 10 g (51 mmol) of 4-methylbenzophenone, 4.9 mL (46 mL (46 mmol) of ethyl cyanoacetate, 0.72 g (9.3 mmol) of ammonium acetate, 2.2 mL (37 mmol) of acetic acid and 8 mL of benzene was heated at reflux for 18 h using a Dean-Stark water separator. Then, 1.1 mL of acetic acid and 0.35 g of ammonium acetate was added and the mixture was heated for 24 h more. The solvent was removed and the residue was dissolved in chloroform and washed with water. The organic phase was dried over magnesium sulfate and the solvent was removed to yield a crude product. This was chromatographed on silica gel (hexane-ethyl acetate mixtures of increasing polarity) to afford 10 g of the title compound of the example as a colourless oil (yield: 67%).