Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])=[CH:16][CH:15]=[CH:14][C:13]=2[OH:28])(=[O:8])[CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[C:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])=[CH:16][CH:15]=[CH:14][C:13]=2[O:28][CH2:2][CH2:3][OH:4])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccc(F)cc1C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
A solution of 2-bromoethanol (5.75 ml, 42 mmol) in acetone (25 ml) was added dropwise to a refluxing mixture of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (1.62 g, 5 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol) and acetone (25 ml) with vigorous stirring. Heating was continued for 18 hours, then water added, the product extracted into dichloromethane, dried and evaporated. Chromatography (silica gel, 2-5% methanol in dichloromethane) and recrystallisation from methanol yielded 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (0.89 g), m.p. 170°-1.72°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([CH2:7][CH:8]([CH3:12])[C:9]([OH:11])=O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>O1CCCC1>[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7][C:5](=[O:6])[C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=1
Reactant: CC(CC(=O)c1cccc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1C(=O)C(C)CC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.10 g. of 3-(4-fluorobenzoyl)-2-methylpropionic acid (Example 2) in 20 ml. of tetrahydrofuran is added 1.62 g. of 1,1'-carbonyldiimidazole. The mixture is stirred at room temperature for one hour, then 1.66 g. of L-proline methyl ester is added and stirring is continued for 18 hours. The mixture is evaporated to dryness in vacuo and the residue is partitioned between dichloromethane and water. The organic layer is separated and washed successively with 1 N hydrochloric acid, water, sodium bicarbonate solution and saline, dried over magnesium sulfate and evaporated to dryness in vacuo giving the desired product as 1.98 g. of a gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[H][H]>[Ni].CO>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:7]2[CH2:6][CH2:5][C:4]([N:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:3][O:2][CH3:1])[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc(N)cc2)CC1

Procedure:
A mixture of 14.8 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is triturated in petroleumether. The product is filtered off and crystallized from a small amount of 2,2'-oxybispropane. It is filtered off and dried, yielding 8.23 parts of N-{1-[2-(4-aminophenyl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide; mp. 106.2° C.
Reaction SMILES: C=C(O[C:5](=[O:13])[NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)C.C1CCN2[C:17](=[N:18]CCC2)[CH2:16][CH2:15]1.C(N)C#C>O1CCOCC1.[Cl-].[Na+].O>[CH2:17]([NH:18][C:5]([NH:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)=[O:13])[C:16]#[CH:15]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C=C(C)OC(=O)NC1CCOCC1
Agent: C#CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C#CCNC(=O)NC1CCOCC1
Temperature: 90 °C
Yield: 81 %

Procedure:
A solution of prop-1-en-2-yl(tetrahydro-2H-pyran-4-yl)carbamate (0.50 g, 2.70 mmol) in dioxane (20 mL) was treated with DBU (0.1 mL) and propargylamine (0.149 g, 2.70 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, treated with brine and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness, treated with Et2O and the resulting solid collected via filtration to afford 1-(prop-2-yn-1-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (400 mg, 81%). 1H NMR (400 MHz, DMSO-d6): δ 6.00 (m, 1 H), 5.99 (m, 1 H), 3.76 (m, 2 H), 3.75 (m, 2 H), 3.56 (m, 1 H), 3.30 (m, 2 H), 3.02 (t, J=2.5 Hz, 1 H), 1.68 (m, 2 H), 1.29 (m, 2H); MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1

Procedure:
Using the synthetic methods described in previous examples, 6-chloro-8-(piperazin-1-yl)quinoline (Example O, step 2, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a white solid; MP. 209-211° C.; MS (ES) m/z (relative intensity) 459 (M+H)+ (100).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH3:13].CN([CH:25]=[O:26])C>C1COCC1>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH:25]=[O:26])[CH3:13]
Reactant: CN(C)C=O
Reactant: CCOc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1cccc(F)c1C=O
Temperature: -65 °C
Reaction time: 0.42 h

Procedure:
1.6M Butyl lithium in hexane (24 ml, 38.4 mmol) was added slowly (0.5 h) to a solution of 1-ethoxy-3-fluorobenzene (5.0 g, 35.7 mmol) in 100 ml of dry THF at -65° C. under nitrogen. The solution was stirred at -65° C. for 25 min. DMF (5.22 g, 71.4 mmol) was added dropwise to the solution. The mixture was allowed to warm to room temperature. 300 ml of ice was poured to this mixture and it was extracted with diethyl ether. Diethyl ether was washed with brine, dried over Na2SO4 and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 2-ethoxy-6-fluorobenzaldehyde.
Reaction SMILES: [Li+].[OH-].[CH2:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][CH:22]([CH2:24][C:25]([O:27]CC)=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[N:10]=1)[CH3:4].C(O)(C(F)(F)F)=O.CC#N.O>C1COCC1.O>[CH2:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[N:10]=1)[CH3:4]
Reactant: CCNc1nc(CCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)OCC)C3)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CCNc1nc(CCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)cs1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.0 N LiOH (0.32 mL, 0.32 mmole) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-[2-[2-(ethylamino)thiazol-4-yl]-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (145.0 mg, 0.32 mmole) in THF (2.4 mL) and H2O (0.48 mL) at 0° C. The resulting pinkish-orange two-phase mixture was stirred at 0° C. for 10 min, during which time the color faded to orangish-yellow, then was warmed to RT. After 1.5 hr, a little more H2O (5 drops) was added, and the reaction was stirred for 42 hr, then was cooled to 0° C. and neutralized with TFA (0.025 mL). The THF was removed on the rotavap, and the resulting oily residue was diluted with 0.1% TFA/CH3CN to give a homogeneous solution. ODS chromatography (gradient: 40% CH3CN/H2O containing 0.1% TFA, then 45% CH3CN/H2O containing 0.1% TFA) gave fractions containing the title compound. These were pooled, and the CH3CN was removed on the rotavap. The resulting aqueous mixture was made basic at 0° C. to afford a homogeneous solution. Careful acidification to pH 4-5 with 1.0 N HCl gave a solid precipitate, which was collected, washed with plenty of H2O, and dried to afford the title compound (80.9 mg, 51%) as an off-white solid: HPLC (Hamilton PRP-1®, 45% CH3CN/H2O containing 0.1% TFA) k′=0.89; 1H NMR (400 MHz, CD3OD) δ7.02-7.18 (m, 4 H), 7.00 (d, J=8.3 Hz, 1 H), 6.79 (d, J=2.6 Hz, 1 H), 6.68 (dd, J=8.3, 2.6 Hz, 1 H), 6.45 (s, 1 H), 4.26 (d, J=14.9 Hz, 1 H), 4.20 (t, J=6.4 Hz, 2 H), 3.87 (d, J=14.9 Hz, 1 H), 3.68-3.80 (m, 1 H), 3.34 (q, J=7.3 Hz, 2 H, partially obscured by residual solvent signal), 3.30 (dd, 1 H, obscured by residual solvent signal), 2.99 (t, J=6.4 Hz, 2 H), 2.92 (dd, J=15.0, 9.4 Hz, 1 H), 2.62 (dd, J=15.9, 5.0 Hz, 1 H), 2.47 (dd, J=15.9, 9.3 Hz, 1 H), 1.27 (t, J=7.3 Hz, 3 H); MS (ES) m/e 423 (M+H)+. Anal. Calcd for C24H26N2O3S.0.67 CF3CO2H: C, 61.03; H, 5.39; N, 5.62. Found: C, 61.21; H, 5.36; N, 5.60.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](OC)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:24]([F:27])([F:26])[F:25])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>>[CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:24]([F:26])([F:27])[F:25])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: OCCc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 82.9 %

Procedure:
Following general procedure E1, methyl 2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.079 g, 0.21 mmol) was reacted with DIBAL (1.0 M, 1.0 mL, 1.0 mmol) to afford the title compound (0.061 g, 83%) as a light yellow oil. MW=350.38. 1H NMR (DMSO-d6, 500 MHz) δ 7.70 (s, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.15 (s, 2H), 3.41-3.33 (m, 1H), 2.68 (t, J=7.0 Hz, 2H), 2.09-1.99 (m, 2H), 1.90-1.61 (m, 6H); APCI MS m/z 351 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24]CC3N4C(CCCC4)=CC=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=1)(=[O:3])[CH3:2].C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1C[CH2:83][N:82]2[C:75](=[CH:76][C:77]3[CH2:78][C:79]([CH3:86])([CH3:85])[CH2:80][C:81]=32)C1=O)(=O)C.BrC1C=C(NC2C=CC(N3CCN(C4COC4)C[C@@H]3C)=CN=2)C(=O)N(C)C=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:47][O:48][CH2:49]5)[CH2:42][C@@H:41]4[CH3:50])=[CH:36][N:35]=3)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=2)=[CH:8][C:9]([F:26])=[CH:10][C:11]=1[N:12]1[CH2:24][CH2:83][N:82]2[C:75](=[CH:76][C:77]3[CH2:78][C:79]([CH3:86])([CH3:85])[CH2:80][C:81]=32)[C:13]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 24 %

Procedure:
Following the procedures as described for compound 101i, reaction of (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate (229 mg, 0.46 mmol) and (S)-5-bromo-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazine-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one (200 mg, 0.46 mmol), afforded 103h as a yellow solid (80 mg, 24%). MS: [M+H]+ 724.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[C:14]1([N:20]2[CH2:24][C:23]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[O:22][C:21]2=[O:30])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:27]3[CH2:26][CH2:25][C:23]4([O:22][C:21](=[O:30])[N:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:24]4)[CH2:29][CH2:28]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: O=C1OC2(CCNCC2)CN1c1ccccc1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CN(c3ccccc3)C(=O)O4)nn2)n1

Procedure:
The object product (72 mg, 29%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (130 mg), 3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (142 mg) and potassium carbonate (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.[OH-].[Na+].O.C(O)(=O)C>C(O)CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[N:15]=2)[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c2nc(C3CC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1-c1nc(C2CC2)n[nH]1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a well stirred slurry of 9-chloro-2-cyclopropyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (5.20 g, 19.9 mmol) in ethylene glycol (40 mL) which was heated to 100° C. was added aqueous sodium hydroxide (10 N, 4 mL, 39.9 mmol). The slurry was heated at reflux for 18 h. After cooling, water (25 mL) was added to the resulted suspension and the pH was adjusted to 6-7 by adding glacial acetic acid (CO2-evolution). The slurry was stirred for 30 min. The solid was collected by filtration and washed with water (3×15 mL). Drying (HV) afforded the title compound (4.05 g, 86%) as a light brown solid. MS: m/e=235.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[O:22]C)=[O:12].B(Br)(Br)Br.CCCCCC.CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22])=[O:12]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(c1ccc(O)cc1O)c1ccc([N+](=O)[O-])cc1O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
(2,4-Dimethoxy-phenyl)-(2-methoxy-4-nitro-phenyl)-methanone (394) (0.4 g, 1.26 mmol) was dissolved in CH2Cl2 and BBr3 was added. The mixture was heated to 40° C. while shaking in a sealed 40 mL I-Chem vial for 16 h. TLC (Rf: 0.5 compared to Rf: 0.65 for compound 394 in 1:1 hexane/EtOAc, single spot) indicated the complete de-methylation at this point. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (395) as a yellow solid upon concentration (0.255 g, 0.927 mmol, 73.5%). The product was used in the next step without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CC(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:37]2[CH2:38][CH2:39][N:34]([C:29]3[N:28]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:35][CH2:36]2)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Yield: 83.7 %

Procedure:
To a compound of N1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide (500 mg, 1.46 mmol) in dry acetone (20 mL) was added anhydrous potassium carbonate (1 g, 7.30 mmol) and 1-(2-pyrimidinyl)piperazine (239 mg, 1.46 mmol). The reaction mixture was refluxed for 24 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. The potassium carbonate was then removed by suction filtration and the solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 6b (575 mg, 83% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1B(O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: OB(O)c1ccccc1CBr
Temperature: 82 °C
Yield: 38.5 %

Procedure:
A suspension of 2-methylphenylboronic acid (10.65 g), N-bromosuccinimide (NBS, 16.86 g) and 2,2′-azobisisobutyronitrile (AIBN, 1.708 g) in carbon tetrachloride (1000 mL) was heated in an oil bath at 82° C. to reflux for 2 hours under anhydrous condition. Cooled the reaction mixture to room temperature and filtered off the solid. Extracted the filtrate with water (2×200 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to dryness. Redissolved the solid in methanol (100 mL) and added ethyl acetate (1000 mL) to it. The resultant precipitate was collected, washed with ethyl acetate (2×50 mL) and dried in the air. The filtrate was concentrated to a small volume and a second crop of solid was also collected. The combined solid was dried in an oven under high vacuum at 50° C. overnight. There was obtained 6.48 g (39%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[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])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:47][CH2:48][OH:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[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])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:47][CH2:48][OH:49])[CH2:36][CH2:37]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCNCC2)N1
Reactant: OCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCN(CCO)CC2)N1
Temperature: 80 °C
Yield: 34 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in ethanol (2 mL) was added triethylamine (45.7 mg, 0.46 mmol) and 2-bromoethanol (42.4 mg, 0.345 mmol) (Aldrich). The reaction mixture was heated at 80° C. for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc:NEt3=12:88:5) to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{2-[1-(2-hydroxy-ethyl)-4-piperidinyloxy]-5-iodo-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 36 mg, 34%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[NH:6][C:5]2([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:13]([F:16])([F:15])[F:14].[NH:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][C:5]2([C:13]([F:14])([F:15])[F:16])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]4[NH:29][N:28]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][C:7](=[O:12])[NH:6]2)=[O:27])=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccc(Br)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1
Reactant: OB(O)c1ccn[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(-c3ccn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1

Procedure:
N-{[6-bromo-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.112 mmol), 1H-pyrazol-5-boronic acid (29 mg, 0.23 mmol), a palladium chloride-1,1-bis(diphenylphosphino)ferrocene complex (18.3 mg, 0.022 mmol) and potassium phosphate trihydrate (60 mg, 0.23 mmol) were suspended in DMF (0.5 mL) and water (0.05 mL), and the mixed solution was stirred at 120° C. for 30 minutes under microwave irradiation. After the reaction solution was left to cool, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC, whereby the objective compound (10 mg, 21%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][C:26]([O:29]C)=[C:25]([F:31])[CH:24]=3)[C@@H:14]([CH3:33])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:31])[CH:24]=3)[C@@H:14]([CH3:33])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)c(F)c2)c2ccccc21
Temperature: 25 °C

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(3-fluoro-4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]acetamide was dissolved in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 mL) was added; the reaction was allowed to stir at room temperature for until no starting material remained. The reaction was washed with sat. NaHCO3 and brine. The organic layer were dried over MgSO4, filtered and concentrated down. The residue was purified by flash chromatography using hexanes-ethyl acetate system to give N-(4-chlorophenyl)-N-[(2S,4R)-1-(3-fluoro-4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]acetamide in decent yield.