Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[O:10][CH:7]([O:8][CH3:9])[C@H:6]([OH:11])[C@@H:5]1[OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]1[O:10][CH:7]([O:8][CH3:9])[C@H:6]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:5]1[O:12][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC[C@H]1OC(OC)[C@H](O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC[C@H]1OC(OC)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of methyl 5-O-methyl-D-ribofuranoside (Dubois L. et al. Tetrahedron 1993, 49(4), 901-910, 2 g, 11.2 mmol) in dimethylformamide (10 mL) was added dropwise to a suspension of sodium hydride (60% in oil, 2.25 g, 563 mmol) in dimethylformamide (54 mL). After stirring at rt for 45 minutes, a solution of benzyl bromide (4 mL, 33.6 mmol) was added dropwise in dimethylformamide (4 mL). The reaction mixture was stirred at rt overnight, quenched with methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexanes/ethyl acetate 70/30 to 50/50) to provide the a anomer (2.86 g, 71%) and the β anomer (0.86 g, 21%); α anomer Rf=0.5, β anomer Rf=0.4 (silica, hexanes/ethyl acetate 50/50).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([N:23]=[N+:24]=[N-:25])[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])[C@H]1CC[C@H](COCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In 50 ml of dry dimethylformamide were suspended 1.70 g of trans-4-benzyloxymethyl-1-(1-methanesulfonyloxyethyl)cyclohexane and 1.69 g of sodium azide, and the mixture was stirred at 110° C. for 30 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed three times with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.48 g of the desired compound as a pale yellow oil. This compound was used for the subsequent reaction without purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([CH3:13])[CH:15]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Reactant: Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1nc(C)c(C#N)c(Nc2cccc(C)c2)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile (500 mg, 2.51 mmol) in DMF (6 mL) were added 3-methylaniline (322 mg, 3.01 mmol) and diisopropyl ethylamine (712 mg, 5.52 mmol), and the reaction mixture was stirred 70° C. for 1.5 h. The mixture was cooled and concentrated, and the residue was dissolved into EtOAc (30 mL) and washed with water (10 mL). The ethyl acetate extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (silica gel, hexane/EtOAc, 0 to 100%) to give the product (650 mg, 96% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19]>>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: CN(C)C(=S)Cl
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccccc1
Yield: 81.8 %

Procedure:
Following the procedure described in Preparation Ia and starting from 9.5 g (0.048 mol) of 2-hydroxyphenyl phenyl methanone and 10.3 g (0.083 mol) of dimethylthiocarbamoyl chloride, 11.2 g of the expected product are obtained (yield: 82%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C1(C)C=CC=CC=1>[CH2:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[N:5][CH:6]=1)[C:12]#[CH:11]
Reactant: CC(=O)c1ccc(N)cn1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCNc1ccc(C(C)=O)nc1
Temperature: 25 °C

Procedure:
2-Acetyl-5-aminopyridine, (Journal of Heterocyclic Chemistry, Vol. 10, pp. 1047-1049 (1973)), 25 g (0.161 mol), is dissolved in 600 ml of dry acetone. To this solution is added an 80% solution of propargyl bromide in toluene, 32 ml, and finely powdered potassium carbonate, 27 g. The solution is heated under reflux for thirty-six hours and then allowed to cool to room temperature. The reaction mixture is concentrated in vacuo and the residue is partitioned between dichloromethane and water. The organic portion is separated and the water layer extracted several times with dichloromethane. The combined organics are concentrated in vacuo to a semi-solid residue consisting of a mixture of starting material and a small amount of the monoalkylated product. The residue is triturated with a mixture of toluene and diethyl ether. The solid is removed by filtration and the filtrate is concentrated to an oil. Chromatography of the oil on silica gel with dichloromethane gives the desired product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reaction time: 18 h
Yield: 42.4 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (263 mg, 1.39 mmol) in THF (3 mL) was added sodium hydride (55% dispersion in mineral oil, 66.7 mg, 1.53 mmol). After stirring for 15 min at room temperature methyl 6-chloronicotinate (286 mg, 1.67 mmol) was added and the reaction mixture was stirred for 18 h. The mixture was then diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic extracts dried over sodium sulfate. Filtration and concentration followed by purification by chromatography (silica, heptane:ethyl acetate 1:0 to 7:3) afforded the title compound (191 mg, 42%) as a colorless oil MS: m/e=325.3 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH2:9]Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I-].[Na+].C(OC[I:21])(=O)C(C)(C)C>CC(C)=O>[C:1]([O:8][CH2:9][I:21])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)OCCl
Reactant: CC(C)(C)C(=O)OCI
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)OCI
Yield: 78 %

Procedure:
Chloromethyl hexanoate (205 mg, 1.25 mmol) was stirred with sodium iodide (900 mg, 6.0 mmol) in 3 mL of dry acetone for 4 hours at room temperature. Work-up followed the procedure detailed in EXAMPLE 3 above for the preparation of iodomethyl pivalate. Iodomethyl hexanoate, CH3 (CH2)4COOCH2I, was obtained as a yellow oil in 78% yield. NMR values were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol), dry pyridine (3 mL), and benzoyl chloride (35 μL, 0.3 mmol) were mixed, and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (methanol/chloroform=1/10) to give the title compound (36 mg, yield 91%) as white powder.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:38](=[O:40])[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:42][CH:41]=2)(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)c1ccc(F)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (100 mg, 0.21 mmol, prepared as described in Step (A) of Example 28) and 4-fluorobenzoic acid (29.5 mg, 0.21 mmol) in 0.3 ml of CH2Cl2, triethylamine (43 mg, 0.42 mmol) and 1-hydroxy-7-azabenzotriazole (31.6 mg, 0.23 mmol) were added and followed by 1,3-diisopropylcarbodiimide (29.3 mg, 0.23 mmol). The reaction was stirred at room temperature for 3 hrs and concentrated. The residue was purified by preparative HPLC on an ODS S10 O column using 31% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 69% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (60 mg, 51%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[CH:5][CH:4]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([CH2:15][CH2:16][C:17]([N:20]2[CH2:27][CH2:26][CH2:25][C@H:21]2[C:22]([OH:24])=[O:23])=[O:19])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)c2ccccc12
Reactant: O=C(O)[C@@H]1CCCN1
Product: COc1ccc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)c2ccccc12

Procedure:
3-(4-Methoxy-1-naphthoyl)propionic acid is coupled to L-proline as described in Examples 15 and 16 to give 1-[3-(4-methoxy-1-naphthoyl)propionyl]-L-proline. The preciding compound is reacted with bromine in acetic acid as in Example 26 and the product reacted with potassium thioacetate in ethanol to give the product of the Example as a glass.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:43]Br)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([C:33]2([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:35][CH2:34]2)[N:27]=3)=[C:20]([F:42])[CH:19]=1>CN(C=O)C>[F:42][C:20]1[CH:19]=[C:18]([CH2:17][CH:16]2[CH2:43][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]2)[CH:23]=[CH:22][C:21]=1[C:24]1[S:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[C:28]([C:33]1([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]1)[N:27]=2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(CC(CBr)CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
To a slurry of sodium hydride (0.206 g, 5.14 mmol) in 7 mL DMF was added diethyl malonate (0.690 mL, 4.57 mmol) dropwise via syringe (bubbling). After 3 min, the reaction mixture was clear, and solid 2-(4-(3-bromo-2-(bromomethyl)propyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.640 g, 1.14 mmol) was added, the reaction mixture was sealed, and heated to 100° C. After 1 h, the reaction mixture was partitioned between sat'd aq. NH4Cl and EtOAc. The org layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, EA/hexanes gradient, to give diethyl 3-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)cyclobutane-1,1-dicarboxylate as a white solid. MS (ESI) m/z: calculated: 558.2; Observed: 559.1 (M++1).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[CH2:15][C:14]2[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(CCC(=O)OC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(CCC(=O)OC)cc2)C(=O)CCC2CCCC2)cc1

Procedure:
The title compound was prepared following the procedure E using of methyl 3-(4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenyl)propanoate and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2. EtOAc/c-Hex 1/1) as a colorless oil (81%). 1H NMR (CDCl3) δ: 7.35-6.93 (m, 8H), 4.47 (s, 2H), 4.34 (s, 1H), 4.31 (s, 1H), 3.61 and 3.60 (2 s, 3H) 2.88 (q, J=7.9 Hz, 2H), 2.55 (q, J=7.2 Hz, 2H), 2.41-2.20 (m, 4H), 1.78-1.12 (m, 21H), 1.10-0.91 (m, 2H), 0.88-0.75 (m, 3H). M+ (ESI): 544.1. HPLC, Rt: 6.6 min (purity: 93.8%).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[C:11]1([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCc2ccccc21
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C1=CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.82 %

Procedure:
To a solution of 1-indanone (23.78 g, 0.18 mol) in 250 mL of ether at 0° C. was added dropwise over 30 min, 100 mL of phenyllithium in ether (1.8M in ether) and the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into a cold saturated ammonium chloride solution, extracted with ether (2×200 mL), and the combined organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure, 70 mL of 20% sulfuric acid in acetic acid was added to the residue and stirred 2 min. To the above solution water (100 mL) and ether (3×200 mL) were added, The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated. Toluene (300 mL) was added to the residue and the mixture was distilled (azeotropic removal of acetic acid) to afford a brown oil. The brown oil was purified by chromatography (silica; (2:1 hexane/methylene chloride)) to afford 15.58 g (45.82%) of 1-phenyl-indene as a colorless oil. In addition 11 g of 1-phenyl-1-acetoxy-indane was isolated as a by-product.
Reaction SMILES: O=O.[CH3:3][C:4](C)([O-])C.[K+].[C:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10].ICC>N#N.O>[CH2:3]([CH:12]([C:13](=[O:15])[CH3:14])[C:9](=[O:11])[CH3:10])[CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)CC(C)=O
Agent: N#N
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCC(C(C)=O)C(C)=O
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a three-neck flask in N2 atmosphere free of water and oxygen were successively added 0.066 mol potassium tert-butoxide and 150 mlTHF. Then to the resulting mixture was slowly added dropwise 0.06 mol acetylacetone with stirring while cooling the mixture with ice-bath. The reaction was allowed to continue at room temperature for 1 hour, then 0.07 mol iodoethane was added dropwise at room temperature. Next, the reaction was allowed to continue at room temperature for further 48 hours. After the reaction was finished, the solvent was removed by distillation. To the solid mixture was added saturated saline until the solid mixture was just completely dissolved. The solution was extracted with suitable amount of anhydrous ethyl ether for three times. The organic phase was combined and dried over anhydrous sodium sulfate. The solvent was removed to give 6.5 g product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>N1C=CC=CC=1>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=4)[CH:12]=[CH:13][CH:14]=3)=[CH:4][CH:3]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (2.00 g, 5.36 mmol) in pyridine (60 mL) was added under ice-cooling 4-methylbenzenesulfonyl chloride (1.12 g, 5.89 mmol), and the mixture was stirred with heating at 80° C. for 2 days. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.75 g, 99%) as a yellow oil. The obtained compound was used in the next reaction without further purification.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C12CCCCC2
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCCC1
Reaction time: 1.25 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 75 minutes while stirring through a solution, cooled to -70°, of 18.4 g of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.55 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 200 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 17.0 g (97%) of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one were obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[CH:19]=[O:20]>>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[C:11]([CH:12]=2)[CH:19]=[O:20])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cc(B(O)O)ccc1F
Reactant: Clc1ccnc(Cl)n1
Product: O=Cc1cc(-c2ccnc(Cl)n2)ccc1F
Yield: 40 %

Procedure:
2,4 dichloropyrimidine and 4-fluoro-3-formylphenylboronic acid was coupled following procedure A. The yield was 40%. LC-MS showed the product was >95% pure and had the expected M+H+ of 237.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19].[F:22][C:23]([F:40])([F:39])[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36]CO)[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH2:21][CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:40])([F:22])[F:39])[CH:25]=2)[CH2:35][CH2:34]1)=[O:19]
Reactant: COC(=O)c1sccc1Nc1ccnc2c(Cl)cccc12
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1sccc1Nc1ccnc2c(Cl)cccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
A mixture of 6.37 g of the product of Step A, 6.17 g of 4-[3-trifluoromethylphenyl]-1-piperazine-ethanol and 50 ml of anhydrous toluene was refluxed for an hour while passing the condensed toluene through a column filled with siliporite and after cooling to 60° C, 150 mg of sodium hydride were added thereto. The mixture was refluxed with stirring for 16 hours and the toluene was distilled. The product was extracted with methylene chloride, washed with water and dried to obtain 11.6 g of 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl 3-(8-chloro-4-quinolylamino)-2-thiophene-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c2[nH]c(=O)oc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c2[nH]c(=O)oc12

Procedure:
A stirred suspension of 4-fluoro-1,3-benzoxazol-2-one-7-carboxylic acid (1.79 g) in dry dichloromethane was treated with oxalyl chloride (0.97 g), followed by N,N-dimethylformamide (3 drops) to initiate the reaction. Stirring was maintained under reflux conditions for 1.5 hours and the mixture evaporated to dryness to give 4-fluoro-1,3-benzoxazol-2-one-7-carboxylic acid chloride, used in the next stage without purification.