Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22].O>C(#N)C>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:9]=[CH:10][C:2]=1[OH:1])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCBr
Reactant: O=C1CCC(c2ccc(O)c(C(=O)O)c2)CC1
Solvent: CC#N
Solvent: O
Product: CCCCCOC(=O)c1cc(C2CCC(=O)CC2)ccc1O

Procedure:
13.60 g (70 mmols) of 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid was suspended in 90 ml of acetonitrile. 10.66 g (70 mmols) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) was added dropwise at 20° C. over a period of 10 minutes, followed by 11.63 g (77 mmols) pentyl bromide over a further period of 10 minutes. The suspension was then stirred under reflux for 18 hours. After cooling the reaction mixture was poured into 300 ml of water and extracted three times with 150 ml of acetic ester. The combined organic phases were washed once with 200 ml 1N HCl, three times with 150 ml of water, dried over magnesium sulphate and filtered. Removal of the solvent gave the crude product which was purified by chromatography on silica gel, eluting with cyclohexane/acetic ester to give 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid pentyl ester.
Reaction SMILES: [CH:1]1([C:4]2[S:25][C:7]3[NH:8][C:9](=[O:24])[N:10](CC4C=CC(OC)=CC=4OC)[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][C:29]=1[F:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:25][C:7]3[N:8]([CH2:27][C:28]4[C:33]([F:34])=[CH:32][C:31]([C:35]5[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][C:29]=4[F:43])[C:9](=[O:24])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Reactant: N#Cc1ccccc1-c1cc(F)c(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A mixture of 6-cyclopropyl-3-(2,4-dimethoxybenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.37 g), 4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (0.38 g), potassium carbonate (0.29 g) and acetonitrile (30 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (10 mL), and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (10 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (10 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.42 g, 94%).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])C=CC=CC=1.CC(C)([O-])C.[K+].CS(O[CH2:31][CH2:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])(=O)=O.[ClH:41].O>O1CCOCC1.C1COCC1.C(OCC)C>[ClH:41].[NH2:8][CH:9]([CH2:31][CH2:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(N)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, 15 g (59.2 mmol) of methyl N-(diphenylmethylene)glycinate [described in: WO2010/123792 A1, 2010; pp. 11-13] were initially charged in 127 ml of 1,4-dioxane, the mixture was cooled to 0° C. and 68.1 ml (68.1 mmol) of a 1 N potassium tert-butoxide solution in THF were added. The reaction solution was stirred at 0° C. for 1 h, 21.2 g (78.7 mmol) of 4,4,5,5,5-pentafluoropentyl methanesulphonate [commercially available; additionally described in: H. Kimura et al. Chemistry and Biology 2010, 17, 18-27] were added and the mixture was stirred at 50° C. overnight. The mixture was cooled to RT, 59.2 ml (118.4 mmol) of 2 N hydrochloric acid in diethyl ether and 2.1 ml (118.4 mmol) of water were added and the mixture was stirred vigorously at RT overnight. The reaction mixture was concentrated and the residue was dried under high vacuum. This gave about 17 g of the target compound as a crude mixture which was used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[CH:20][C:19]=4[F:26])=[C:11]3[C:10]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:19]([F:26])=[CH:20][C:21]([NH:25][C:51]([C:48]5[C:49](=[O:50])[N:44]([C:41]6[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=6)[N:45]=[CH:46][CH:47]=5)=[O:52])=[C:22]([Cl:24])[CH:23]=4)=[C:11]3[C:10]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[N:9]2)=[CH:35][CH:36]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
A solution of 1-(4-methoxybenzyl)-4-(4-amino-5-chloro-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (130 mg, 0.254 mmol) in CH2Cl2 (1 mL) was added into a solution of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (119 mg, 0.509 mmol, obtained from Example 19 Step C), triethylamine (0.213 ml, 1.53 mmol), EDCI (293 mg, 1.53 mmol) and HOBT (206 mg, 1.53 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred for 12 hours at ambient temperature. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The organic layer obtained was dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (100 mg, 54.1% yield) as a yellow solid. LRMS (APCI pos) m/e 727.2 (M+H).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]3[C:21]4([CH2:36][O:37][C:17]=3[CH:16]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:22]4=[O:35])C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1.C(=O)(O)[O-].[Na+]>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]2[C:21]3([CH2:36][O:37][C:17]=2[CH:16]=1)[C:29]1[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=1)[N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:22]3=[O:35]
Reactant: CCCCCN1C(=O)C2(COc3cc(N=C(c4ccccc4)c4ccccc4)ccc32)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C2(COc3cc(N)ccc32)c2ccccc21
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a solution of 6-[(diphenylmethylene)amino]-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1H)-one in anhydrous tetrahydrofuran (4.00 mL) was added aqueous 10% hydrochloric acid (2.00 mL). The reaction mixture was stirred for 15 min, diluted with aqueous sodium bicarbonate (5.00 mL) and extracted with ethyl acetate (3×25.0 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.02 g, 24% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.26 (td, 1H), 7.12 (d, 1H), 6.99 (dd, 1H), 6.89 (d, 1H), 6.43 (d, 1H), 6.23 (d, 1H), 6.08 (dd, 1H), 4.86 (d, 1H), 4.60 (d, 1H), 3.86-3.60 (m, 2H), 1.77-1.65 (m, 2H), 1.41-1.30 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 171.2, 162.1, 148.7, 142.5, 133.1, 128.6, 127.8, 123.9, 123.7, 123.0, 118.5, 108.5, 108.4, 97.2, 80.2, 77.6, 77.4, 77.2, 76.8, 64.0, 60.4, 57.6, 40.3, 29.7, 29.0, 27.1, 22.6, 22.4, 22.1, 19.1, 14.2, 14.0, 13.7; MS (ES+) m/z 323.5 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>C(=O)([O-])[O-].[Na+].[Na+].O>[C:17]([N:13]1[C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:13]1[C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:24]
Reactant: O=C(Cl)CCCCCC(=O)Cl
Reactant: N#Cc1cccc(C2N[C@H](C(=O)O)CS2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(C2SC[C@@H](C(=O)O)N2C(=O)CCCCCC(=O)N2C(c3cccc(C#N)c3)SC[C@H]2C(=O)O)c1
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a stirred solution of (4R)-2-(3-cyanophenyl)-4-thiazolidinecarboxylic acid (4.7 g) in 1M sodium carbonate (30 ml), heptanedioyl dichloride (2.1 g) was added dropwise under ice-cooling. The reaction mixture was stirred for 30 minutes at the same temperature, and filtered to give the precipitates. The precipitates were dissolved in hot water (100 ml), and acidified with concentrated hydrochloric acid. The separated crystals were collected by filtration to give 3.5 g (59%) of the titled compound: mp 105°-112° C.; [α]D25 +115.0° (c=1.0, methanol). IR (nujol, cm-1): 2270 (CN), 1735 (COOH), 1640 (CON), 1610 (aromatic), 1195, 790 (aromatic). NMR (DMSO-d6) δ: 0.69-1.66 (6H, m, --CH2 --CH2)3CH2 --), 1.70-2.50 (4H, m, --CH2 --CH2)3CH2 --), 2.85-3.66 (4H, m, C5 --H), 4.69 (1H, dd, J=8.2, 6.0 Hz, C4 --H), 5.13 (1H, m, C4 --H), 6.16 (1H, s, C2 --H), 6.43 (1H, s, C2 -- H), 7.3-8.3 (8H, m, arom. H). TLC: Rf value* 0.33.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:12].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([CH3:36])([CH3:35])[CH:33]=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.[BH3-]C#N.[Na+]>C(Cl)Cl>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([C:32]([CH3:36])([CH3:35])[CH2:33][NH:1][C:2]2[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=2[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(C(=O)c2ccc(C(C)C)cc2)c(N)cc1O
Reactant: COc1cc(OC)cc(C(C)(C)C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC)cc(C(C)(C)CNc2cc(O)c(OC)cc2C(=O)c2ccc(C(C)C)cc2)c1
Reaction time: 16 h

Procedure:
A mixture of 41.1 mg (144 μmol) (2-amino-4-hydroxy-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 45 mg (216 mmol) 2-(3,5-dimethoxy-phenyl)-2-methyl-propionaldehyde, 180 mg molecular sieves (pore size 4 Å) and 0.50 ml CH2Cl2 is stirred for 90 min before 8.23 μl (144 μmol) and 22 mg NaCNBH3 are added. After 16 h the excess of reducing agent is destroyed by addition of 1 M hydrochloric acid and the mixture is basified with 1 M sodium hydroxide solution. The product is extracted with CH2Cl2 and purified by reversed phase preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: Cc1ccccc1I
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-n1ccc(C)c(N2CCc3nc(N)ncc3C2)c1=O
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (0.025 g, 0.097 mmol), 1-iodo-2-methylbenzene (20 mg, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (6 mg, 0.049 mmol), copper iodide (5 mg, 0.020 mmol), and potassium phosphate (41 mg, 0.194 mmol) in 0.5 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (17 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and with NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using a CHCl3/EtOAc gradient. Upon reaching a 1:1 mixture of EtOAc and CHCl3, 3% MeOH was added and increased up to 6% MeOH. After concentrating the appropriate fractions, a white solid was collected as the pure product (8 mg, 24%). 1H NMR (DMSO) δ: 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.46 (m, 1H), 7.28-7.35 (m, 2H), 6.28 (s, 2H), 6.17 (m, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.21 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1.S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([C:17]([OH:21])=[O:18])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)c2c3ccccc3n(C)c12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)c2c3ccccc3n(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of 1-methoxy-9-methyl 9H-4-carbazolecarbaldehyde (100 mg 0.4184 mmoles) in a mixture of 8 mL acetone and 4 mL water, sulfamic acid (48.7 mg 0.502 mmoles) was added followed by a solution of sodium chlorite (37.8 mg, 0.4184 mmoles) in 2 mL water and the reaction mixture was stirred at 25° C. for 4 hrs. Acetone from the reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate 30 mL. Organic layer was separated and basified with freshly prepared sodium bicarbonate solution and separated the aqueous layer and acidified with 1N HCl and extracted with ethyl acetate (2×25 mL). Ethyl acetate layer was washed with brine (2×20 mL), dried over sodium sulfate and concerted to give 95 mg of the tide compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19](I)=[CH:20][C:12]1=2)=[O:10].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])=[CH:36][CH:35]=3)=[CH:20][C:12]1=2)=[O:10]
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C(c1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(C(=O)c3cc(F)ccc3F)CCN4)cc2)CC1
Yield: 36 %

Procedure:
(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone (35 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a light yellow solid (36% yield). M.p. 201-203° C., LCMS: m/z=478.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.33-2.52 (m, 4H), 3.40-3.85 (m, 8H), 5.31 (s, 1H), 6.70-7.05 (m, 3H), 7.15 (s, 1H), 7.24-7.45 (m, 4H), 8.09 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].O=C(C)C[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC(=O)COc1cccc2cccnc12
Product: O=C(COc1cccc2cccnc12)c1ccc(Cl)cc1
Yield: 76 %

Procedure:
8-(2-(p-Chlorophenyl)-2-oxoethoxy)quinoline (9a) was prepared from 2-bromo-4'-chloroacetophenone by the same procedure as 7a in 76% yield. mp: 111°-112° C.; 1H -NMR (CDCl3): δ5.56 (s, 2H, OCH2), 6.96-8.96 (m, 10 H, Ar--H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[OH2:33]>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:33])=[CH:4][CH:3]=1
Reactant: O
Reactant: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of NaIO4 (5.9503 g, 27.82 mmol) in water (40 mL) was added RuCl3 hydrate (0.0526 g, 0.25 mmol) followed by a solution of crude N-(6′-bromo-β-(1-ethoxyvinyl)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-yl)-2-(trimethylsilyl)ethanesulfonamide (9) (1.0894 g), obtained as described above, in EtOAc (60 mL). The resulting mixture was vigorously stirred at room temperature for 30 min and LC-MS indicated the disappearance of starting material. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers was dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford ethyl 6′-bromo-4-methoxy-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (10) (0.5329 g, 50% in two steps). LC-MS tR=2.27 min in 3 min chromatography, m/z 568, 570 (MNa+), 333, 335; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 4.41-4.25 (m, 2H), 3.32 (s, 3H), 3.08-3.02 (m, 2H), 2.80 (d, J=15.8 Hz, 1H), 2.16-2.04 (m, 3H), 1.91-1.87 (m, 2H), 1.80-1.72 (m, 1H), 1.40-1.22 (m, 7H), 0.95-0.88 (m, 1H), 0.80-0.72 (m, 1H), 0.65-0.57 (m, 1H), −0.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.13, 142.21, 140.91, 132.97, 132.25, 126.52, 119.45, 78.49, 75.10, 61.87, 55.79, 53.06, 50.92, 38.15, 28.64, 28.38, 28.33, 27.82, 14.18, 9.98, −2.28.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N>[CH3:15][O:14][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[C:11]([O:12][CH3:13])[C:2]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)c1cc(OC)c(-c2ccccc2)c(OC)c1

Procedure:
PdCl2(dppf) (14.8 g) was added to a CH3CN (900 mL) solution of methyl 4-bromo-3,5-dimethoxybenzoate (25.0 g), phenylboronic acid (22.2 g), Bu4NBr (5.86 g) and K3PO4 (77.2 g), and stirred under heat for 14 hours. This was filtered through Celite, and the filtrate was concentrated and purified through column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1
Reactant: CCc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCc1nc(Cl)cc(NN)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred, cold (0° C.) solution of 60 g (0.34 mole) of 4,6-dichloro-2-ethylpyrimidine in 500 ml of methanol was added 35 g (0.7 mole) of hydrazine hydrate while maintaining the temperature below 10° C. Stirring was continued for 2 hours after completion of the addition, the temperature being maintained at 0° C. The mixture was allowed to warm to about 20° C. and was stirred for 16 hours. The white solid was collected by filtration and the filtrate was partially evaporated to provide a second crop. The combined solids were washed with water and air dried to provide 51 g (77%) of 4-chloro-2-ethyl-6-hydrazinylpyrimidine, m.p. 147°-150° C.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].BrCC1C=CC=C([Cl:26])C=1>>[ClH:26].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:1])[CH:12]=2)[C:4]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: N[C@H]1CCCCN(Cc2ccccc2)C1=O
Agent: Cl
Product: N[C@H]1CCCCN(Cc2cccc(Cl)c2)C1=O

Procedure:
(S)-3-Amino-1-(3-chlorobenzyl)azepan-2-one hydrochloride (190 mg, 0.657 mmol) was synthesized as described for the preparation of Intermediate 42 using 1-(bromomethyl)-3-chlorobenzene in step A.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.CCCCCC>[CH2:28]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][CH:9]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1cccc(NCc2ccccc2)c1

Procedure:
The title compound is prepared from N-(3-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamid dihydrochloride (Example 183) and benzaldehyde according to the method described in Example 177. Melting Point: 98-100° C. (diethylether-hexane)