Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1.ClC(OCC(C)C)=O.N1CCCC1>ClCCl>[N:17]1([C:10]([CH:9]2[CH2:13][CH2:14][CH2:15][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:12])[CH2:22][CH2:21][CH2:19][CH2:18]1
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(C1CCCN1Cc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 1-benzyl-L-proline (50 g) in dichloromethane (300 ml) is cooled with ice. To the solution is added N-methylmorpholine (22.5 g), and then further thereto is added dropwise isobutyl chloroformate (30 g). The mixture is stirred at the same temperature for about one hour, and thereto is added dropwise pyrrolidine (18.8 ml) at the same temperature. The mixture is warmed to room temperature, and stirred for two days. The mixture is washed twice with water (250 ml), and dried over magnesium sulfate. The mixture is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(1-pyrrolidinyl)carbonyl-1-benzylpyrrolidine (31 g), as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(OC(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-methoxy-5-trifluoromethoxybenzoic acid (0.6 g, 2.53 mmol) and dichloromethane (10 mL). Cool in an ice bath. Add dropwise oxalyl chloride (0.64 mL, 5.0 mmol) followed by dimethylformamide (1 drop). Warm to ambient temperature. After 3 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [CH3:1][C@:2]1([CH2:13][CH:14]=[O:15])[CH2:4][C@H:3]1[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].COC1CCCC1.[BH4-].[Na+].S(=O)(=O)(O)O>CO>[CH3:1][C@:2]1([CH2:13][CH2:14][OH:15])[CH2:4][C@H:3]1[CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CC(c1ccccc1)[C@@H]1C[C@]1(C)CC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COC1CCCC1
Solvent: CO
Product: CC(c1ccccc1)[C@@H]1C[C@]1(C)CCO
Temperature: 20 °C
Yield: 94 %

Procedure:
under a nitrogen atmosphere, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetaldehyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol), cyclopentyl methyl ether (4 ml), and sodium borohydride (0.05 g, 1.3 mmol) were placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and methanol (0.05 g) was added with stirring at 20° C., followed by stirring at the same temperature for 60 minutes. Next, a 5% aqueous sulfuric acid solution (1.3 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]ethanol (a diastereomer mixture with a component ratio of 1:2, 0.19 g, 0.93 mmol, 94% yield).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH2:25][CH2:26][N:27]5C(=O)C6=CC=CC=C6C5=O)[CH:17]=4)[C:12](=[O:38])[C:11]=3[CH:10]=2)C(=O)C2=CC=CC=C12.O.NN.Cl>CO.O>[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19](=[O:23])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH2:25][CH2:26][NH2:27])[CH:17]=3)[C:12](=[O:38])[C:11]=2[CH:10]=1
Reactant: O=C1c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2C(=O)c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc21
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NCCOc1ccc2c(c1)C(=O)c1ccc(OCCN)cc1C2=O
Temperature: 0 °C

Procedure:
A mixture of 17.4 g (0.03 mole) of the intermediate 2,6-bis-(2-phthalimidoethoxy)anthraquinone, prepared in (A) above, 200 ml. of methanol, and 3.6 g. (0.06 mole) of hydrazine hydrate (85% is heated to reflux for 4 hours. Water (100 ml.) is added and the methanol boiled out of the mixture. Then, 75 ml. of 37% hydrochloric acid is added and the resulting mixture heated to reflux for another hour. The mixture is allowed to cool, then chilled at 0°C., and the precipitate of phthalhydrazide removed by filtration with suction. The filtrate is evaporated to dryness, made alkaline with 10% sodium hydroxide, and the base is extracted into chloroform. The chloroform layer is washed with water, dried with anhydrous magnesium sulfate, filtered, and the chloroform evaporated. The 2,6-bis-(2-aminoethoxy)anthraquinone base is converted to the dihydrochloride salt as described in Example 1, and recrystallized from a solvent or solvent mixture such as isopropanol, ethanol/ether, or butanone/methanol. In a similar manner, 2,7-bis(2-aminoethoxy)anthraquinone can be prepared from 2,7-bis(2-chloroethoxy)anthraquinone.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([NH2:24])=[O:23].Br[CH2:26][CH2:27][O:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].O.O.C(O)(=O)C(O)=O>C(OCC)(=O)C.[Cl-].[Na+].O.O.CO.CN(C)C=O>[CH2:27]([O:28][CH2:29][CH2:30][N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:22]([NH2:24])=[O:23])=[CH:6]2)[CH3:26]
Reactant: COCn1c(C(N)=O)cc2cccc(NS(=O)(=O)c3cccs3)c21
Reactant: CCOCCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 75 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (6.25 g), 1-bromo-2-ethoxyethane (3.41 g), potassium carbonate (7.09 g) and N,N-dimethylformamide (30 ml) was stirred at 75° C. for 6 hr. The reaction mixture was diluted with ethyl acetate and saturated brine. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-hexane (2:1) mixture to give a solid. A mixture of this solid (5.50 g), oxalic acid dihydrate (4.77 g), methanol (50 ml) and water (50 ml) was stirred at 90° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the obtained solid was crystallized, and washed with water to give the title compound (4.70 g, yield 95%) as crystals. melting point 135° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[C:10]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)Nc2ccc(Oc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(O)c(C(=O)Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 83 %

Procedure:
3-Benzyloxy-6-methoxy-4′-phenoxypicolinanilide was suspended in 5 ml of ethanol. 10% palladium-carbon (30 mg) was added to the suspension. The mixture was subjected to catalytic reduction under atmospheric conditions overnight. The reaction solution was filtered, and the filtrate was concentrated under the reduced pressure. The residue was then purified by column chromatography on silica gel (chloroform) to give the title compound (yield 83%).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:23]=1
Reactant: ClC(Cn1ccnc1)c1cccnc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
192 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to 4 ml of dry dimethylformamide containing 740 mg of methyl 4-mercaptobenzoate, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. 830 mg of 1-[2-chloro-2-(3-pyridyl)ethyl]imidazole in 4 ml of dry dimethylformamide were added to the reaction mixture, and the resulting mixture was heated at 60°-70° C. for 5 hours. At the end of this time the reaction mixture was treated and purified by the same method as described in Example 1, to give 615 mg of the title compound as an oil.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=O)[NH:40][N:39]=2)=[CH:33][CH:32]=1.N>C(Cl)(Cl)Cl.O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[N:39][N:40]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.19 g (0.1 mol) phosphorus pentoxide, 13.77 g (0.1 mol) triethylamine hydrochloride and 12.76 g (0.1 mol) 4-chloroaniline is heated and stirred in a nitrogen atmosphere at 200° C. until a homogeneous melt has formed (about 20 min). To the melt, 5.93 g (0.025 mol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone (for preparation see German Auslegeschrift no. 1 061 788 [published Jul. 23, 1959]) is added, and the reaction mixture is stirred for 3 h at 200° C. After the reaction mixture has cooled to about 100° C., 200 ml of water is added. Stirring is continued until the temperature reaches about 30° C., and then 20 ml conc. ammonia (30% aqueous ammonium hydroxide solution) and 900 ml chloroform are added consecutively. As soon as a diphasic mixture has formed, the organic phase is separated off, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated on a RE to a volume of about 50 ml, to which 100 ml acetate is then added, and the mixture is cooled in an ice bath. The crystallizate obtained is filtered off and washed with acetate and ether. After recrystallization from methanol and drying under HV for 8 h at 120° C., the title compound is obtained; m.p. 194-195° C.; ESI-MS: (M+H)+=347.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[S:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=[C:2]1[NH:1][C:12](=[O:13])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Nc1nc2c(s1)CCCC2
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4,5,6,7-tetrahydrobenzothiazole (12.3 grams; 0.08 mol) dissolved in pyridine (50 ml.) was charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. Ethyl chloroformate (12 ml; 0.11 mol) was added dropwise to the reaction mixture with stirring and cooling. After the addition was completed the reaction mixture was allowed to warm to room temperature and stirring was continued for a period of about 1 hour. After this time the reaction mixture was poured into ice water (50 mol.) to form a precipitate. The precipitate was recovered by filtration, washed with water four times dried and recrystallized from ethanol to yield the desired product ethyl N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate; (16.7 grams); melting point 182°-184° C. The structure of the product was verified by infrared and NMR spectroscopy.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:13]([Cl:14])=[C:12]([N+:15]([O-:17])=[O:16])[C:11](Cl)=[CH:10][C:8]=1N.N([O-])=O.[Na+].[Cl:23]CCl>C(O)C.C(=O)([O-])O.[Na+]>[Br:6][C:7]1[C:13]([Cl:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[C:10]([Cl:23])[CH:8]=1
Reactant: ClCCl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])c(Cl)c1Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(Br)c1Cl
Yield: 80 %

Procedure:
Concentrated sulphuric acid (2.2 ml) was slowly added to a suspension of 2-bromo-3,5-dichloro-4-nitroaniline (D8) (0.9 g, 3.1 mmol) in ethanol (20 ml). The resulting solution was heated to reflux and crushed sodium nitrite (478 mg, 6.9 mmol) was added in two portions. After 0.5 h at reflux, the mixture was cooled, diluted with dichloromethane (50 ml) and saturated sodium hydrogen carbonate solution (50 ml) was added. The layers were separated and the organic phase dried (Na2SO4) and concentrated to an oil which was purified by column chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to give the title compound (D9) as an orange solid (0.67 g, 80%), MH+ 269/271.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:16]([O:17][CH3:18])=[CH:15][C:13]([NH2:14])=[C:12]([Cl:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32].C(OCC)(=O)C>O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][C:31]([NH:14][C:13]1[CH:15]=[C:16]([O:17][CH3:18])[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][C:12]=1[Cl:19])=[O:32]
Reactant: O=C(Cl)CCCBr
Reactant: COc1cc(N)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)CCCBr)c(Cl)cc1CO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyaniline (intermediate 39; 0.75 g, 2.48 mmol) in tetrahydrofuran (20 mL) and triethylamine (0.38 mL, 2.73 mmol) was added under nitrogen atmosphere at 0° C. 4-bromobutanoyl chloride (0.32 mL, 2.76 mmol). The mixture was stirred for half an hour. Ethyl acetate was added to the mixture and the organic layer was washed with bicarbonate and brine, dried and the solvent was removed under reduced pressure. The title compound was obtained (97%) and it was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2([CH2:37][CH2:36][CH2:35]2)[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[N:26]1([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2([CH2:37][CH2:36][CH2:35]2)[CH2:27]1
Reactant: c1ccc2c(c1)NCC21CCC1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC2(CCC2)c2ccccc21

Procedure:
214 mg (0.63 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 100 mg (0.628 mmol) spiro[cyclobutane-1,3′-indoline], 212 mg (0.66 mmol) TBTU and 168 μL (1.20 mmol) triethylamine in 4 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and the acetonitrile was removed using the rotary evaporator. The precipitated substance was suction filtered, washed with 20 mL water and dried in the CAD at 50° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[C:7]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:5]=2[CH:6]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[C:7]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:5]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Yield: 73 %

Procedure:
To a solution of ethyl 2-methyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (252d) (226 mg, 0.604 mmol) and NBS (183 mg, 1.03 mmol) in CHCl3 (10 mL) was added benzoyl peroxide (14.6 mg, 0.0604 mmol). After stirring the mixture at refluxed for 4 hr, the solvent was evaporated. The product was purified by gradient silica gel chromatography with hexanes/EtOAc (100/0 to 70/30) to give the title compound (200 mg, 73%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.39 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 4.53 (s, 2 H) 6.62 (s, 1 H) 7.05-7.18 (m, 2 H) 7.62 (d, J=0.75 Hz, 1 H) 7.86-7.98 (m, 2 H) 8.07 (d, J=0.75 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH:14]=C)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].N1C=CC=CC=1.[O:22]=[O+][O-].S(C)C>C(Cl)Cl.CO>[C:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH:14]=[O:22])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc(C(=O)OC)c(C#N)c1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CC=O)cc1C#N
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The methyl 2-cyano-4-(prop-2-en-1-yl)benzoate (100 mg, 0.5 mmol) was dissolved in 1:1 CH2Cl2/MeOH (20 mL) containing pyridine (0.25%). The solution was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (3 mol) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and evaporated to give methyl 2-cyano-4-(2-oxoethyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:5].[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]1[O:5][C:20](=[O:21])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(NNc1ccccc1Cl)c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2Cl)nn1-c1ccccc1Cl
Temperature: 59 °C

Procedure:
39 g (0.13 mol) of 2-chloro-6-fluoro-N'-(o-chlorophenyl)-benzhydrazide are treated with a solution of 40 g (0.40 mol) of phosgene in 275 ml of toluene and the mixture is heated to reflux temperature (internal temperature 59° C.) for 2.5 hours. A further 13 g (0.13 mol) of phosgene in 70 ml of toluene are added thereto and the reaction mixture is heated to reflux temperature for a further 2.5 hours. The excess phosgene and toluene are distilled off, and the residue is taken up in 500 ml of diethyl ether and the solution is washed with semisaturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrystallization of the crude product from a mixture of diethyl ether and n-hexane there is obtained pure 5-(2-chloro-6-fluorophenyl)-3-(2-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 92°-95° C.; IR spectrum: 1790 cm-1 ; mass spectrum: 324(12), 280 (10), 125(100).
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40].O>C(Cl)Cl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCS(=O)(=O)Oc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex. 2, Step 1 (320 mg, 0.72 mmol) in 10 ml CH2Cl2 was cooled to 0° C. Triethylamine (100 μl, 0.72 mmol) was added followed by 1-propanesulfonyl chloride (81 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added, the mixture extracted with CH2Cl2 (3×20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2) afforded 220 mg (56%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3S(C2C=CC(C)=CC=2)(=O)=O)=[O:10])=[CH:5][CH:4]=1.[C-]#N.[Na+].Cl>CS(C)=O>[NH:15]1[C:16]2[C:12](=[C:11]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[O:10])[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: COc1ccc(C(=O)c2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(c1ccc(O)cc1)c1cccc2[nH]ccc12
Yield: 61.2 %

Procedure:
A solution of 56.1 g of the product of Step C, 66.16 g of sodium cyanide and 370 ml of dimethylsulfoxide was heated for 16 hours at 140° C. and then the solution was allowed to return to ambient temperature. 1500 ml of 2N hydrochloric acid were added and extraction was done with sulfuric ether. The extracts were concentrated to dryness under reduced pressure and the 70.4 g residue were chromatographed on silica (eluant: methylene chloride - ethyl acetate (85-15) to obtain 20.1 g of the desired product melting at 177° C. which was used as is for the following step. After chromatography on silica of 5.5 g of the above product (eluant: ethyl acetate - n-hexane (4-6)) and crystallization of the residue from ethyl acetate - n-hexane, 3.96 g of pure product melting at 177° C. were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10]2[O:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Cc1coc(CNc2cnccc2I)n1
Product: COc1cc(F)ccc1-c1ccncc1NCc1nc(C)co1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((4-methyloxazol-2-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 23 hours at reflux. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), then EtOAc:MeOH (100:0 to 90:10). Off-white solid (88%). MS (ESI): m/z=314.130 [M+H]+.