Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+]>O1CCOCC1.O>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:11](=[O:14])[O:12][C:6]([CH3:8])([CH3:7])[CH3:5])=[CH:7][C:6]=1[CH2:8][OH:9]
Reactant: Nc1ccc(Cl)c(CO)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CO)c1
Reaction time: 3 h
Yield: 136.9 %

Procedure:
To a solution of (5-amino-2-chlorophenyl)methanol (Aldrich, 500 mg, 3.17 mmol) in a mixture of dioxane (7.5 mL), water (7.5 mL) was added sodium carbonate (336 mg, 3.17 mmol) previously dissolved in 4 mL of water. Solution was stirred and cooled in an ice bath. Boc-anhydride (Aldrich, 692 mg, 3.17 mmol) was added in one portion, and stirring was continued at room temperature for 3 h. Dioxane was removed in vacuo conditions and the aqueous layer chilled, covered with a layer of ethyl acetate, and acidified to pH 4 with dilute KHSO4 (10%, aq) (ALDRICH). This was followed by extraction (EtOAc) and purification by chromatographic column 25 g cartridge (ISOLUTE silice) using Hex/EtOAc 100/0 to 50/50, giving 1,1-dimethylethyl [4-chloro-3-(hydroxymethyl)phenyl]carbamate (560 mg, 2.17 mmol, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.46 (br s, 1H), 7.72 (s, 1H), 7.21-7.32 (m, 2H), 5.35 (t, 1H), 4.48 (d, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27]O)[CH2:23][CH2:22]1)C1C=CC=CC=1>C1COCC1.C([Li])CCC>[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=2[O:12][CH3:13])[CH2:23][CH2:22]1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.1 %

Procedure:
1,1-carbonyldiimidazole (0.8 g., 0.005 mol) was added to a solution of 4-amino-5-chloro-2-methoxy-benzoic acid (1 g, 5 mmol) in THF (20 ml) and the reaction mixture was stirred at room temperature for about 30 minutes. The solvent was evaporated and the residue was taken up in H2O and extracted into ethyl acetate (3×20 ml). The organic phases were collected, dried and evaporated to dryness. The obtained solid residue was dissolved in THF (10 ml) and dropped into a solution of 1-benzylpiperidin-4-yl-methanol [J. Med. Chem. (1992), 35, 4344], (1 g, 5 mmol) in THF (10 ml) and butyllithium (1.6 M in hexane; 3 ml), maintained at 0° C. The reaction mixture was further stirred at room temperature for 1 hour. The solvent was evaporated and the residue was taken up into H2O and extracted into ethyl acetate. The organic extracts were dried and evaporated to give the desired product as a pale yellow oil, (1.63 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11]>N1C=CC=CC=1>[CH3:8][N:9]([CH3:13])[C:10]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:11]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(N)no1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)N(C)C)no1
Yield: 56 %

Procedure:
To 3-amino-5-methylisoxazole (490.6 mg), pyridine (3 g) and dimethylcarbamoyl chloride (1.18 g) are added, and the resultant mixture is stirred at 60° C for 5.5 hours. The pyridine is evaporated under reduced pressure. The residue is mixed with water (15 ml), adjusted to pH 1 with 5% hydrochloric acid and shaken with chloroform. The chloroform layer is evaporated to remove the chloroform. The residue is mixed with 1.5% methanolic sodium hydroxide solution (25 ml) and evaporated. The residue is extracted with chloroform again. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the chloroform. The residue is chromatographed on a thin layer of silica gel to give 1,1-dimethyl-3-(5-methyl-3-isoxazolyl)urea (0.4735 g) as crystals melting at 150.5° to 151.5° C. The yield is 56%.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35](O)=[O:36])[CH2:29][CH2:28]2)=[CH:22][C:21]=1[C:38]([F:41])([F:40])[F:39])([O-:19])=[O:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:28][CH2:29][CH:30]([O:33][CH2:34][C:35]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:16]=[CH:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[N:8]=4)[CH2:6][CH2:5]3)=[O:36])[CH2:31][CH2:32]2)=[CH:22][C:21]=1[C:38]([F:39])([F:40])[F:41])([O-:19])=[O:18]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 2-(piperazin-1-yl)quinoline (150 mg, 0.70 mmol) in dichloromethane (30 ml) was added 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (300 mg, 0.83 mmol, 1.2 eq), EDAC.HCl (201 mg, 1.05 mmol, 1.5 eq), HOBt (142.6 mg, 1.06 mmol, 1.5 eq) and triethylamine (213 mg, 2.10 mmol, 3 eq). The resulting solution was stirred overnight at room temperature, quenched by the addition of water (50 ml), and then extracted with dichloromethane (3×50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC using 5% methanol in dichloromethane to elute. The product-containing fractions were combined and then concentrated under vacuum to afford 229 mg (580) of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-(quinolin-2-yl)piperazin-1-yl]ethan-1-one as a yellow solid. (ES, m/z): [M+H]+ 558.40; 1H NMR (300 MHz, CDCl3): δ 7.94-8.03 (1, 2H), 7.71 (s, 1H), 7.55-7.65 (1, 2H), 7.28-7.30 (t, J=5.4 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.65 (m, 1H), 4.51 (d, J=7.5 Hz, 1H), 4.27 (s, 2H), 3.74-3.96 (1, 8H), 3.34-3.51 (1, 2H), 2.14-2.17 (1, 4H), 1.50-1.60 (m, 2H), 1.36-1.47 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][CH:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NC1CCC(O)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCC(O)CC3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-aminocyclohexanol via General Procedure E to give 11.1 mg of 281 following reverse phase purification. MS (Q1) 477.2 (M)+
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc(C2OCCO2)n1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 6-bromo-pyridine-2-carbaldehyde (2.0 g, 10.75 mmol), ethylene glycol (3 mL, 53.75 mmol), and a catalytic amount of TsOH in toluene (50 mL) was heated to reflux with a Dean-Stark trap for 1.5 hours and cooled down to room temperature and concentrated in vacuo. The residue was purified on silica gel column with 2% EtOAc in CH2Cl2 to yield 2-bromo-6-[1,3]dioxolan-2-yl-pyridine as a colorless liquid (1.97 g, 80%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:29])=[C:4]([C:21]([OH:28])=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[O:16][C:17]([F:20])([F:19])[F:18])=[O:6].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[C:3]([CH3:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]=2[OH:28])=[O:6])=[C:9]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)#[N:15]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C#N)cc2)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-bromo-5-tert-butyl-N-(2-trifluoromethoxy-4-cyano-phenyl)-6-hydroxy-2-methyl-benzamide (0.141 g, 0.3 mmole) in dioxane (5 ml) under nitrogen, 4-cyanophenylboronic acid (44.0 mg, 0.3 mmole), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmole) and sodiumcarbonate (1.05 ml, 2 M solution in water) were added. The reaction mixture was heated at 100° C. for 6 hours. The reaction mixture was evaporated, diluted with ethyl acetate and the organic phase was washed with citric acid solution (10%). The organic phase was dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26]N=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.O1C=[N:33][N:32]=[C:31]1C1C=CC(N)=CC=1>>[O:26]1[CH:31]=[N:32][N:33]=[C:22]1[C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13]2[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[NH2:1])[N:14]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(-c2nnco2)cc1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2nnco2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(1,3,4-oxadiazol-2-yl)aniline in step 1. MS: 395.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:17][CH2:16][C:13]1([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11][N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1
Reactant: COc1ncccc1CN1CCC(CO)(CCc2ccccc2)CC1
Reactant: Oc1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(CCc2ccccc2)(COc2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
After dissolving 55 mg of 1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-methanol, 51 mg of triphenylphosphine and 20 mg of 2-fluorophenol in 10 ml of tetrahydrofuran, the solution was cooled to 0° C. 0.13 ml of diethyl azodicarboxylate (40% toluene solution) was then added dropwise and the mixture was stirred overnight at room temperature. After stirring for 5 hours at 70° C. and cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (5 mg, 7% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:12](=[O:13])[CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCc2ccc([N+](=O)[O-])cc2)cc1
Yield: 81.3 %

Procedure:
A procedure similar to step 2 of Example 1 was used, the 3-(4-nitro-phenyl)-propionyl chloride prepared in the step 2 and methylphenyl ether were used as starting materials, and anhydrous AlCl3 was used as catalyst, the obtained product was white solid in a yield of 81.3%, mp: 123-125 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.18 (2H, t, J=7.00 Hz), 3.30 (2H, t, J=7.00 Hz), 3.87 (3H, s, OCH3), 6.93 (2H, d, J=8.96 Hz, ArH), 7.42 (2H, d, J=8.60 Hz, ArH), 7.93 (2H, d, J=8.96 Hz, ArH), 8.15 (2H, d, J=8.60 Hz, ArH); EI-MS m/e (%): 285.0 (M+, 62), 134 (100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:28]([O-])([O-])([O-])[O:29][CH2:30][C:31]([F:34])([F:33])[F:32]>>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=[C:28]2[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: [O-]C([O-])([O-])OCC(F)(F)F
Product: COC(=O)c1cccc2nc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 25 %

Procedure:
The title compound was prepared as pale yellow crystals from methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate and 2,2,2-trifluoroethyl orthocarbonate according to the procedure for Working Example 3. Yield: 25%, m.p. 143°-145° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.[Mg].II.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: COc1c(C)cc(Br)cc1C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c(OC)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,6-dimethylanisole (PREPARATION 1, 12.98 g) in tetrahydrofuran (40 ml) is added drop by drop to a mixture of magnesium turnings (1.87 g) in tetrahydrofuran (5 ml). The Grignard reaction is initiated with iodine crystals. After the addition is complete, the mixture is refluxed for 2 hours. The Grignard reagent is cooled to about 10° and then a solution of ethyl chloroformate (7.5 ml) in tetrahydrofuran (40 ml) is added in a 2 minute period. The mixture is stirred for 45 minutes at ice-water temperature and then at 20°-25° for 2 hours. The reaction is quenched with a saturated solution of ammonium chloride and diluted with ether. The phases are separated, the organic phase is washed with water and then with saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:17]=[N:18][C:19]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:11][C:8]2[N:6]4[CH:7]=[C:2]([C:36](=[O:38])[CH3:37])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)=[CH:21][CH:20]=3)[CH2:23][CH2:24]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN1CCN(c2cnc3ccc(Sc4nnc5ccc(Br)cn45)cc3c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCN(C)CC5)cc4c3)n2c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of (86.1) (80 mg, 0.176 mmol) and PdCl2(PPh3)2 (12.3 mg, 0.018 mmol) in dioxane (6 ml) was bubbled by N2 for 10 min, then tributyl(1-ethoxyvinyl)stannane (127 mg, 0.351 mmol) was added and the solution was heated at 110° C. under N2 for 3 hours in oil bath. The reaction mixture was quenched with KF solution and extracted with EtOAc for three times. The combined extract was washed with brine and dried over anhydrous Na2SO4. Solvent was evaporated and the crude was dissolved in MeOH (10 ml). Drops of 3N HCl solution were added and the solution was then stirred at rt for 4 hours. Solvent was evaporated and the residue was purified on flash chromatography (gradient eluent: MeOH/DCM from 0-10%) to afford the title compound as yellow solid (0.16 g, >100%, contains some impurities). LCMS (method A): [M+H]+=419.2, tR=1.45 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1.[CH:22]([C:24]1[C:25]([OH:38])=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)=[O:23].O>CN(C)C=O>[CH:22]([C:24]1[C:25]([O:38][CH2:8][C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:34])([CH3:35])[C:32]=2[CH:33]=1)=[O:23]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(O)cc21
Reactant: CCOC(=O)c1ccc(C#CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
0.71 g of potassium carbonate and 1.0 g of ethyl 4-(3-bromo-1-propynyl)benzoate were added to 20 ml of a solution of 0.80 g of 3-formyl-5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene in anhydrous N,N-dimethyl formamide at room temperature. The obtained mixture was stirred at 50° C. for 30 minutes, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% diethyl ether/n-hexane) to give 0.87 g of the title compound as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8](CCO)[C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(CCO)c1cc(Cl)ccc12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 70.9 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (0.09 g, 0.175 mmol) prepared in example 56b in methanol (10 mL) was added N,N′-diisopropylethylamine (2 mL, 11.1 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.06 g, 70.6%).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[N:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[N:10]=1.[CH3:17][OH:18]>>[F:16][C:11]1[CH:12]=[C:13]([F:15])[N:14]=[C:9]([O:18][CH3:17])[N:10]=1
Reactant: CO
Reactant: Fc1cc(F)nc(F)n1
Solvent: CCN(CC)CC
Product: COc1nc(F)cc(F)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
3.8 g (0.0373 mol) of triethylamine were added at -20° C. to a mixture of 5 g (0.0373 mol) of 2,4,6-trifluoropyrimidine in 50 ml of methanol within 5 minutes, and the mixture was stirred at this temperature for a further 40 minutes. After the reaction was complete, the mixture was warmed to 25° C. and the excess methanol was removed by distillation under reduced pressure. The residue obtained in this way was partitioned between methylene chloride and water, and the organic phase was dried over magnesium sulfate and concentrated. 4.6 g (85% of theory) of an isomer mixture which, according to investigation by gas chromatography, contained 46% of the title compound and 48% of 4,6-difluoro-2-methoxypyrimidine were obtained in this way.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26]([OH:28])=O)([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:25])([CH3:24])[C:26]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:28])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCN(C)CC3)c1)N2
Yield: 90.8 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), 1-methyl-piperazine (0.67 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 24 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-{3-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.895 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C29H40N4O3 (M+H)+: 493.67, observed: 493.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[N:8][CH:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH:30]([Cl:33])([Cl:32])[Cl:31]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[N:8]([C:4]([O:3][CH2:1][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:5])[C:9]([CH3:13])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC(Cl)(Cl)Cl)C1c1ccccc1[N+](=O)[O-]
Yield: 45 %

Procedure:
1.0 g (3.3 millimole) of 5-Ethoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)dihydropyrimidine was dissolved in 20 ml of chloroform and 2 ml of triethyl amine (14.3 millimole) was added to the solution with stirring and then 0.9 ml (6.54 millimole) of 2,2,2-trichloroethoxychloroformate was added dropwise. After stirring for one hour, the reaction mixture was concentrated under reduced pressure and the residue was purified on silica gel by column chromatography (eluant: methylene chloride) to obtain 0.71 g (45% yield) of title compound.