Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C>[CH2:36]([O:35][CH2:34][CH2:33][O:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](O)[C@H]2OC(C)(C)O[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](OCCOCc2ccccc2)[C@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)carbamate (3.0 g, 10.8 mmol) in dry DMF (30 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 530 mg, 13.0 mmol). After stirring for 30 min at 0° C., 2-(benzyloxy)ethyl 4-methylbenzenesulfonate (3.3 g, 10.8 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (30 mL). To the mixture was extracted 3×30 mL of n-hexane. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIIc was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
After 33.3 g (0.25 mol) of 5-aminoindane (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 250 ml of glacial acetic acid, the solution was heated at 50° C., and 51.0 g (0.5 mol) of acetic anhydride was added dropwise. After the termination of the dropping, stirring was performed for 4 hours. After the termination of the reaction, the reaction solution was poured into 1500 ml of ice water with stirring. Precipitated crystals were separated by filtration, and washed with 1000 ml of water. The resulting crystals were dried to obtain 37.06 g of 5-(N-acetylamino)indane (yield: 84.6%, melting point: 100.5 to 103.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:25]([O-:27])=[O:26])[CH2:13][CH2:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39](O)[CH2:40][OH:41]>C1CCCCC1>[CH2:40]1[O:41][C:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([CH2:14][CH2:13][CH:12]([N+:25]([O-:27])=[O:26])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:24][CH2:39]1
Reactant: OCCO
Reactant: COc1ccc(CC(CCC(=O)CCc2ccccc2)[N+](=O)[O-])cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: COc1ccc(CC(CCC2(CCc3ccccc3)OCCO2)[N+](=O)[O-])cc1OC

Procedure:
Into a 1 l r.b. flask equipped with a Dean Stark trap was placed 46.4 g (0.12 m) of 1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanone, 1.5. g p-toluenesulfonic acid, 50 mL of ethylene glycol and 300 mL of cyclohexane. The mixture was allowed to reflux overnight, then concentrated in vacuo. Dil NaHCO3 solution was added to the residue and extracted with ethyl acetate. The organic layer was backwashed with water, dried over anh. MgSO4, filtered and concentrated under reduced pressure to give 45.3 g of an oil which solidified on drying at room temperature under vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:19]=2)[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(Oc2cccc(C#N)c2C#N)c1
Yield: 80 %

Procedure:
1,2-dicyano-3-nitrobenzene (1.73 g) and 3-tert-butyl-hydroxybenzene (4.50 g) were allowed to react with each other at 80° C. for 2 hours in dimethylformamide (DMF, 5 ml) with the addition of K2CO3 (5.0 g). After the completion of the reaction, the reaction product was extracted twice with a mixed solvent of water and ethyl acetate (at a volumetric ratio of 1/1), and the layer extracted with ethyl acetate was dried overnight with the use of MgSO4, followed by removal of ethyl acetate by distillation. The residues were isolated and purified by silica gel column chromatography using chloroform to obtain 2.21 g of 1,2-dicyano-3-(3-tert-butylphenyloxy) benzene in a 80% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: ClCc1cccnc1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCc3cccnc3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-(chloromethyl)pyridine hydrochloride, whereby the product was isolated as free base, 2-methyl-7-(pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline as a red solid. ISP mass spectrum, m/e: 320.4 (M+1 calculated for C22H21N3O: 320).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:12]([C:4]3[CH:3]=[C:2]([OH:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[O:14])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: O=C(c1cc(O)c2ccccc2n1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 4-hydroxyquinoline-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].C(N[C:16]1[CH:25]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[C:23]([O:30]C(=O)C)=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:34])=[N:21]2)(=O)C>C(O)(=O)C.O>[C:27]([NH:26][C:24]1[C:23](=[O:30])[C:22]2[N:21]=[C:20]([CH3:34])[CH:19]=[CH:18][C:17]=2[C:16](=[O:2])[CH:25]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1cc(NC(C)=O)c2ccc(C)nc2c1OC(C)=O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 56 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. Into a 1000 ml Erlenmeyer flask, 240 ml of glacial acetic acid, and 5,7-diacetamido-2-methyl-8-acetoxyquinoline (31) (prepared as described in Example 31) (6.3 g, 2.0 mmol) were added. To the resulting suspension, a solution of potassium dichromate (17.64 g) in 200 ml of water was added. This black solution was magnetically stirred at room temperature for 20-24 hours. The solution was then poured into 900 ml of water and extracted with dichloromethane (5×200 ml). The organic extracts were washed with a solution of 5% sodium carbonate in a saturated salt solution (3×300 ml). The organic layer was dried overnight with anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the solvent was evaporated to leave an orange/yellow solid. The solid 7-acetamino-2-methylquinoline-5,8-dione (27) was dried overnight under vacuum. 2.6 g of product was obtained for a yield of 56%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1.[Br:20]Br>C(O)(=O)C.Br>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH:10]([Br:20])[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2F)cc1
Agent: Br
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of the ketone intermediate from Step 2 (2.05 g, 7.4 mmol) in acetic acid (30 mL) and 33% HBr in acetic acid (0.5 mL) was treated with a 0.99M solution of bromine in acetic acid (7.6 mL, 7.5 mmol) and stirred at room temperature for 1 hour. The solution was concentrated in vacuo and the residue was taken up in dichloromethane, washed with 1N NaHSO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a brown solid (2.39 g, 90%) that was unstable and used directly in the next step without further purification. 1H NMR (CDCl3) 300 MHz 7.94 (q, J=6.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.97 (m, 1H), 6.84 (m, 1H), 6.28 (s, 1H), 2.46 (s, 3H); 19F NMR (CDCl3) -100.31 (m), -103.50 (m). Mass spectrum: M+H=358.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].CC([O-])(C)C.[K+].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:27]=[C:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:25][C:24]=2[S:32]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=1>CS(C)=O.C(Cl)Cl>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:27]=[C:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:25][C:24]=3[S:32]([NH:35][C:36]([CH3:38])([CH3:37])[CH3:39])(=[O:33])=[O:34])[CH:20]=[CH:21][CH:22]=2)[C:3]1=[O:4]
Reactant: CN1CC(=O)NC1=O
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Cc1cc(-c2cccc(CN3C(=O)CN(C)C3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 1-methylhydantoin (33.9 mg, 0.297 mmol) in DMSO (1 mL) and t-BuOK (46.6 mg, 0.415 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (87.9 mg, 0.198 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:petroleum ether (35:65) as eluent to give the sub-title compound in 54% yield as a colourless syrup (51.5 mg, 0.107 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][O:16]C(Cl)Cl>ClCCCl.[N+](C)([O-])=O>[CH:15]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)=[O:16]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1cc(C=O)c[nH]1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of ethyl pyrrole-2-carboxylate (8.1 g, 58.3 mmol) and AlCl3 (15.5 g, 2 equiv) in 1,2-dichloroethane-nitromethane (1:1, 120 ml) was added α,α,-dichloromethyl methyl ether (6.4 mL, 2 equiv) dropwise at −20° C. Stirring was continued for 1 h at −20° C. and the reaction mixture was stored at −20° C. overnight. It was then poured into ice. Organic layer was separated and aqueous layer was extracted with DCM. The combined organic layers were washed with water, aqueous NH4OH and water and dried over Na2SO4. Evaporation of solvent afforded ethyl 4-formylpyrrole-2-carboxylate as a solid (8.8 g, 90%). 1H-NMR(CDCl3): δ 10.40 (1H, s), 8.95 (1H, s), 7.60 (1H, dd), 7.33 (1H, dd), 4.36 (2H, q), 1.39 (3H, t).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([Cl:16])=[CH:13][C:14]=1[I:15])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:16][C:12]1[N:11]=[CH:10][C:9]([NH:7][CH3:6])=[C:14]([I:15])[CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To the solution of tert-butyl(6-chloro-4-iodopyridin-3-yl)(methyl)carbamate (62.5 g, 0.172 mol) in 500 mL of anhydrous DCM was added 180 mL of TFA. Then the solution was stirred at room temperature for 4 hrs. Concentrated to remove the solvent, and purified by flash chromatography to afford 45.1 g 6-chloro-4-iodo-N-methylpyridin-3-amine as a yellow solid (Yield: 97.3%).
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH2:15]([Sn:17](Br)([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:16]>CCOCC>[CH2:15]([Sn:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:7]1[O:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[CH3:16]
Reactant: CC[Sn](Br)(CC)CC
Reactant: c1ccc2ocnc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1nc2ccccc2o1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6M, 6.0 mL, 9.57 mmol) was added to a solution of benzoxazole (950 mg, 7.98 mmol) in anhydrous ether (20 mL) stirred at −78° C. under nitrogen. After 10 min, triethylstannyl bromide (2.28 g, 7.98 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound as a brown oily residue which was used directly without further purification for the next step.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:4]=2[NH:3]1.[OH-].[Na+]>C(O)C.C1COCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:4]=2[NH:3]1
Reactant: COC(=O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirring solution of compound 119 (0.856 g, 3.11 mmol) in ethanol (16 mL) and THF (8 mL) was added an aqueous solution of sodium hydroxide (5 mL, 31.3 mmol) and the resulting mixture was stirred at 55° C. for 2 h. The reaction mixture was solvent evaporated to one third volume, acidified with 3N HCl to pH 2 and the resulting white precipitate was filtered to afford 120 (0.801 g, 99%) as a beige solid. LRMS (ESI): (calc) 261.01. (found) 262.1 (MH)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:3]([CH:14]([OH:16])[CH3:15])[O:4][C:5]2=[O:13])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(O)c1oc(=O)c2cc(Cl)ccc2c1Br
Product: CC(O)c1oc(=O)c2cc(Cl)ccc2c1-c1ccccc1
Yield: 38.9 %

Procedure:
The title compound was made in a similar way of that of Intermediate B53 from 4-bromo-7-chloro-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A5, 1.4 g, 4.61 mmol) and phenylboronic acid (0.844 g, 6.92 mmol) to afford title compound as a yellow foam (0.540 g) which was used without any additional purification.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[C:45]([OH:6])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(CCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(CCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)acetic acid (4.8 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)ethanol instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 8.21 (d, J=8 Hz, 1 H), 7.93 (s, 1 H), 7.7-7.6 (m, 4 H), 7.37 (d, J=8 Hz, 1 H), 7.3-7.15 (m, 5 H), 5.24 (s, 1 H), 3.46 (d, J=7.6 Hz, 2 H), 3.18 (d, J=7.6 Hz, 2 H), 2.76 (s, 3 H), 0.96 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C30H31ClNO3: 488.2. Found: 488.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=[O:15].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 94.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 13.1 g (0.24 mol) of methanesulfonic acid (produced by Tokyo Chemical Industry Co., Ltd), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-epoxypyrrolidine (yield 94.7%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:32][CH2:31]3)[CH2:22][CH2:21]2)=[O:19])=[CH:6][C:5]=1[Cl:33].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:33][C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:31][CH2:32]3)[CH2:22][CH2:21]2)=[O:19])[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:34])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a suspension of 3.68 g (7.38 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid methyl ester (Example 27) in 40 mL dioxane and 40 mL water were added 0.387 g (9.22 mmol) lithium hydroxide mono hydrate. The reaction mixture was stirred 1.5 hours at room temperature upon which a yellow solution formed. Dioxane was removed by evaporation and the resulting suspension was diluted with 50 mL water and the pH was adjusted to 1 using 10 mL 25% aqueous hydrochloric acid. The resulting suspension was stirred for approx. 2 hours at room temperature, filtered, washed with water and dried under high vacuum to give 3.49 g (97%) of the desired compound as a light brown solid. MS (ESI): m/z=484.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1cc(Nc2cccc3[nH]ccc23)ncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
4,6-Dichloropyrimidine (1.01 g, 6.6 mmol), 4-aminoindole (900 mg, 6.6 mmol) and N,N-diisopropylethylamine (3.14 ml, 18 mmol) were dissolved in N,N-dimethylformamide (20 ml), and the reaction mixture was stirred at 80° C. for 6 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; and a small amount of methanol was added to the residue to crystallize; and the crystals were filtered off, washed with methanol and ethyl acetate, and dried under aeration to yield the title compound (599 mg, 2.5 mmol, 37%) as pale brown crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1>>[CH3:9][C@@H:10]1[N:15]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1
Reactant: O=Cc1cccnc1
Reactant: C[C@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1
Product: C[C@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1Cc1cccnc1
Yield: 62 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(3S)-3-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(3S)-3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)#[CH:13].N>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: N
Product: COc1cc(OC)cc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3,5-dimethoxybenzene (Aldrich, 81 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 83.87 (s, 6H), 6.64 (t, J=2.2 Hz, 1H), 7.06 (d, J=2.4 Hz, 2H), 7.40 (s, 1H), 8.16 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.96 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 301 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31].[C:32](OCC)(=[O:37])[CH2:33][C:34]([CH3:36])=O.N>O>[CH3:36][C:34]1[NH:20][C:21]2[C:30]([C:32](=[O:37])[CH:33]=1)=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[CH3:31]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: CCOC(=O)CC(C)=O
Agent: N
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COC(=O)c1cc(C)c2[nH]c(C)cc(=O)c2c1
Temperature: 140 °C
Yield: 42.9 %

Procedure:
A mixture of phosphorus pentoxide (37 g) and phosphoric acid (46 g) was heated under stirring in an oil bath at 140° C., and methyl 4-amino-3-methylbenzoate (3.0 g) and ethyl acetoacetate (2.8 g) were added thereto, followed by heating under stirring for an additional 2 hours. The reaction mixture was cooled to 60° C., poured into water, and neutralized with a 29% aqueous ammonia solution, and the precipitate was collected by filtration to obtain methyl 2,8-dimethyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.8 g).