Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:5][CH2:4]1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[N:13]=[C:14]([NH:16][C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:29])[S:15][C:11]=1[C:9]([CH:6]1[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]1)=[O:10]
Reactant: O=C(O)c1ccncc1
Reactant: COC1CCC(C(=O)c2sc(N)nc2-c2ccco2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
Compound 441 (579 mg, 1.89 mmol) was dissolved in THF (9.0 mL), and isonicotinic acid (931 mg, 7.57 mmol), EDC hydrochloride (1.45 g, 7.57 mmol) and 1-hydroxybenzotriazole monohydrate (1.16 g, 7.57 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 442 (664 mg, 85%).
Reaction SMILES: BrC1C=CC=CC=1O.C[C:10]1[C:15]2O[C:17]3[C:25]([OH:26])=[C:24]([OH:27])[CH:23]=[C:22]([OH:28])[C:18]=3[C:19](=[O:21])[CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1>C1(C)CCC(C(C)C)C(N(C2C(C(C)C)CCC(C)C2)C=O)C1.CCOCC.[OH-].[Na+].CCCCCC.[Cu].[Cu](I)I.C(=O)([O-])[O-].[K+].[K+]>[OH:27][C:24]1[C:25]([OH:26])=[CH:17][C:18]2[C:19](=[O:21])[CH2:20][C:14]3[CH:15]=[CH:10][CH:11]=[CH:12][C:13]=3[O:28][C:22]=2[CH:23]=1
Reactant: Cc1cccc2c1Oc1c(O)c(O)cc(O)c1C(=O)C2
Agent: I[Cu]I
Agent: [Cu]
Agent: CC1CCC(C(C)C)C(N(C=O)C2CC(C)CCC2C(C)C)C1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1Cc2ccccc2Oc2cc(O)c(O)cc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 298.3 %

Procedure:
To a solution of 2-bromophenol (380 mg) in N,N-dimenthylformamide (2.5 ml) were added potassium carbonate (15 mg), copper (19.5 mg), copper iodide, (15 mg) and 6-bromo-3,4-dimethoxyacetophenone (Compound 4) (130 mg) and the mixture was stirred at 100° C. for four hours. The reaction mixture was diluted with ether and 5% aqueous solution of sodium hydroxide was added thereto followed by stirring for five minutes. This was diluted with a mixture of ether and hexane and was washed with 5% aqueous solution of sodium hydroxide, water and saturated sodium chloride solution successively. The organic layer was collected and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The resulting residue was purified by a silica gel chromatography (hexane:ether=3:1) to give the title compound (345 mg, 80%) as yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:14]([OH:20])([C:16]([F:19])([F:18])[F:17])=[O:15].C(Cl)Cl>>[F:17][C:16]([F:19])([F:18])[C:14]([OH:20])=[O:15].[CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CNC1

Procedure:
A solution of tert-butyl 3-methoxyazetidine-1-carboxylate (270 mg, 1.44 mmol) in 1:1 TFA/DCM (1 mL) was stirred at ambient temperature for 1 hour and concentrated. The crude product was directly used in the next step assuming quantitative yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N)CN>>[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:14]([O:13][Si:9]([CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O:16][CH2:17][CH3:18])[O:10][CH2:11][CH3:12])[CH3:15]
Reactant: CCO[Si](CCl)(OCC)OCC
Solvent: NCCN
Solvent: C1COCCN1
Product: CCO[Si](CN1CCOCC1)(OCC)OCC
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
82 g of dry morpholine (pKb 5.67) were heated to 120° C. in a 500 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer and 80 g of chloromethyltriethoxysilane were added in the course of 180 min with stirring. After the end of the addition, the temperature was reduced to 105° C. and 226.6 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min and the heavier ethylenediamine hydrochloride phase was then separated off. The upper phase was subjected to fractional distillation without a distillation column. 37 g (45% recovery) of morpholine having a purity of 89.7% and 73.5 g (yield 74.2%) of 4-(triethoxysilylmethyl)-tetrahydro-1,4-oxazine were obtained, the purity of which was determined as 97.3%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[O:13][CH2:12]1.[OH-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][CH:11]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:20]2=[O:21]
Reactant: COc1ccc2c(c1)C(=O)C(Br)CO2
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(Oc1cccnc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.6 %

Procedure:
To a room temperature solution of 3-hydroxypyridine (7.55 g, 0.0778 mol) in dimethylformamide (400 ml) was added in portions 3.74 g (0.0780 mol) of 50% sodium hydride. The mixture was stirred at room temperature for 30 minutes, followed by the addition of 20.0 g (0.0778 mol) of 3-bromo-6-methoxy-4-chromanone all at once. The resulting red-orange mixture was stirred at room temperature for 1 hour, after which tlc (20% ethyl acetate/CH2Cl2) indicated complete conversion of starting material to the more polar products. The reaction mixture was poured into 1.2 liter of H2O, adjusted to pH 8-9 with 1N NaOH and extracted with ethyl acetate (2×800 ml). The combined extracts were washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo to a yellow oil. Purification by flash column chromatography using 2.3 Kg of fine mesh silica gel and eluting with 20% ethyl acetate/CH2Cl2 afforded title product as a pale yellow solid in 3.6% yield, m.p. 135-136° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[N:6][S:5][N:4]=1.[C-:15]#[N:16].[Na+].O>CN(C)C=O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]([CH2:2][C:15]#[N:16])=[N:4][S:5][N:6]=1
Reactant: [C-]#N
Reactant: Clc1ccccc1-c1nsnc1CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1nsnc1-c1ccccc1Cl
Yield: 63.7 %

Procedure:
In N,N-dimethylformamide, 290 mg of 3-bromomethyl-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 49 mg of sodium cyanide were stirred at 90° C. for 3 hours. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole. The obtained 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole, 6 mL of 5% sodium hydroxide solution, and 2 mL of ethanol were mixed and refluxed by heating for one hour. After spontaneous cooling, the reaction mixture was poured into dilute hydrochloric acid, and was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of [3-(2-chlorophenyl)-1,2,5-thiadiazole-4-yl]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[N:9]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:18])[NH:11][C:12]([CH3:17])=[C:13]2[C:14](=[O:16])[NH:34][CH2:33][CH2:32][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1C(=O)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)NC(C)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
109 mg (0.309 mmol) of 4-(3-chlorophenyl)-3-ethoxycarbonylmethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 97.9 mg (0.463 mmol) of 3,3-diphenylpropylamine were dissolved in 20 ml of dichloromethane. 88.8 mg (0.463 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[I:11]I.[I-].[K+]>[NH4+].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[I:11]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: II
Agent: [I-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 51 %

Procedure:
4.08 g (corresponding to 30.0 mmol) of 4′-hydroxyacetophenone was dissolved in 250 mL of 28% aqueous ammonium solution, and a solution of 7.61 g (corresponding to 30.0 mmol) of iodine and 24.3 g (corresponding to 146 mmol) of potassium iodide in 60 mL of water was added thereto. The resulting solution was stirred at room temperature for 22.5 hours. After the completion of the reaction, the reaction mixture was concentrated, diluted with water, and then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed once with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. To the resulting concentrates, 60 mL of water and 40 mL of 8 mol/L sodium hydroxide solution were added, sufficiently mixed, and filtered to remove insoluble matters. Then, conc. hydrochloric acid was added to the filtrate to make it acidic, and the precipitates were filtered and dried under reduced pressure. The resulted precipitates were dissolved in a mixed solution of chloroform and ethyl acetate, and then water was added thereto, and extracted with chloroform for five times. The combined chloroform layers were dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure, to obtain 4.00 g (corresponding to 15.3 mmol) of 4′-hydroxy-3′-iodoacetophenone (FIG. 3, Step 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.O[C:17]1[N:22]=[CH:21][C:20]2[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][C:19]=2[CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:17]3[N:22]=[CH:21][C:20]4[C:23](=[O:29])[N:24]([CH:26]([CH3:27])[CH3:28])[CH2:25][C:19]=4[CH:18]=3)=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)N1Cc2cc(O)ncc2C1=O
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc2c(cn1)C(=O)N(C(C)C)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.6 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (251 mg, 1.21 mmol) in THF (30 mL) was added 6-hydroxy-2-isopropyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (232 mg, 1.21 mmol) and triphenylphosphine (413 mg, 1.58 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (624 μL, 1.58 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (141 mg, 31%) as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[5-(piperidino)valeryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and δ-piperidinovaleric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C:4]1=[O:10])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].ClCCl>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[C:5]1=[O:9])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CCN1CCNC(=O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(CC)C(=O)C1=O
Yield: 72 %

Procedure:
As described for example 119a, 1-ethyl-piperazine-2,3-dione was reacted with sodium hydride followed by reaction with ethyl bromoacetate. Aqueous workup followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 94:4) afforded the title compound as a light yellow oil (yield: 72%). MS: m/e=229.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:2]2[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
an oven dried flask was added 4-bromo-naphthalene-1-carboxylic acid In (1.36 g, 0.0054 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL) and aluminum trichloride (0.676 g, 0.0051 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[Cl:25][C:23]1[CH:24]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([N:7]3[CH:8]=[CH:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]3)[CH2:14]2)[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: COC(=O)c1ccn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of methyl ester of example 18.1 (408 mg) in 5 ml THF:water (4:1) was added sodium hydroxide (60 mg). The reaction was stirred 2 hours at room temperature before evaporation of the solvent in vacuo. The aqueous layer was extracted with ethyl acetate before being acidified. It was then extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford the title acid (369 mg) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz): 8.20 (s, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 7.05 (s, 1H), 4.45 (d, 1H), 4.10 (d, 1H).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC(CSCCO)=CC=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2ccc(CSCCO)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 99 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (3.11 g, 9.83 mmol, 1 eq.) in anhydrous THF (100 mL) was treated with phenol (1.29 g, 13.76 mmol, 1.4 eq.), triphenylphosphine (3.61 g, 13.76 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (2.78 g, 2.71 mL, 13.76 mmol, 1.4 eq.) as described. When the reaction was complete, the reaction was worked up and the product purified via silica gel flash chromatography leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester (3.82 g, 99% yield) as a yellow oil.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[CH2:12]Br>CO>[Br:11][C:9]1[CH:10]=[C:5]2[C:6]([CH2:12][NH:1][C:4]2=[O:3])=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: N
Solvent: CO
Product: O=C1NCc2ccc(Br)cc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[CH:7][C:6]([CH3:10])=[N:5]2)[CH2:3][CH2:2]1.[CH:11]1([C:14](=O)[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1>C(O)(=O)C>[CH:1]1([N:4]2[C:8]3[N:9]=[C:14]([CH:11]4[CH2:12][CH2:13]4)[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=3[C:6]([CH3:10])=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C2CC2)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CC1

Procedure:
1-cyclopropyl-3-methyl-1H-pyrazol-5-amine (300 mg, 2.187 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (403 mg, 2.187 mmol) and acetic Acid (40 mL) were heated at reflux for 2 hours. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: 0 to 11% EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.13 (m, 4 H), 1.16-1.21 (m, 2 H), 1.25-1.30 (m, 2 H), 1.46 (t, J=7.20 Hz, 3 H), 2.16-2.31 (m, 1 H), 2.63 (s, 3 H), 3.78 (m, J=7.26, 7.26, 3.79, 3.66 Hz, 1 H), 4.47 (q, J=7.24 Hz, 2 H), 7.40 (s, 1 H). LCMS(ES) [M+H]+ 286.2
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[F:58]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=2[F:58])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N)CN2C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](Nc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
(2S,4S)-1-Boc-4-amino-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine (10.61 g, 33.96 mmol) obtained in Step C was dissolved in toluene (100 mL). Sodium t-butoxide (3.73 g, 38.81 mmol), 2-(di-t-butylphosphino)biphenyl (863 mg, 2.89 mmol), Tris(dibenzylideneacetone)-dipalladium(0) (1.73 g, 1.93 mmol) and 1-bromo-2,4-difluorobenzene (7.48 g, 38.81 mmol) were added thereto and the reaction solution was stirred for 10 hours at 110° C. After the reaction was completed, solid like material was filtered using the Cellite from the reaction solution. The reaction solution was diluted with EtOAc and washed with water. The extracted organic solution was dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent: MC:MeOH=10/1) to give the title compound (11.24 g, 78%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([SiH2:11][O:12][C:13]([CH3:25])([CH3:24])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:17]=[N:18]O)([CH3:10])([CH3:9])[CH3:8].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[C:7]([SiH2:11][O:12][C:13]([CH3:25])([CH3:24])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:17][NH2:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=NO)ccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
LiAlH4 (4.11 g, 108 mmol) was added in portions to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzaldehyde oxime (13.0 g, 43.4 mmol) in Et2O (433 mL). The mixture was stirred for 1 h at rt. Aq. sat. potassium sodium tartrate (400 mL) was carefully added to the mixture. The mixture was stirred for 3 h, and was extracted with Et2O (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the crude title compound (12.4 g, quantitative yield) that was used further without purification. LC-MS: tR=0.84 min; ES+: 327.37.