Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH:29]([CH3:31])[CH3:30])[C:17]1=O.CCN(CC)CC.[Si](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH:29]([C@H:18]1[N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21][N:16]2[C:3]3[CH:4]=[C:5]([S:12]([CH3:15])(=[O:13])=[O:14])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=3[N:1]=[C:17]12)([CH3:30])[CH3:31]
Reactant: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (25 g, 0.0532 mol) in dichloromethane (500 mL) were added Et3N (64.5 g, 0.638 mol, 12 eq.) and SiCl4 (27.1 g, 0.160 mol, 3 eq.). The mixture was stirred at rt overnight. The mixture was added dropwise to aq. NaHCO3 solution (54.1 g in 1 L of water, 0.644 mol, 12.1 eq.) at 0° C. slowly and adjusted to pH=8. The mixture was filtered and the aqueous layer was extracted with dichloromethane (3×600 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under vacuum to give the residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether: EtOAc 2:1 to give (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (13.2 g, 55% yield) as a pale yellow solid. Analytical chiral HPLC: tR=9.03 min in 15 min chromatography (Method: OD-3—3—5—40—2.5 ML). LC-MS MS (ESI) m/z 452.2 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.31 (s, 1H), 8.01 (s, 1H), 5.30-5.18 (m, 1H), 4.70-4.52 (m, 1H), 4.47 (dd, J=3.2 and 12.4 Hz, 1H), 4.18 (dt, J=5.2 and 11.6 Hz, 1H), 3.98 (s, 3H), 3.70-3.52 (m, 1H), 3.44 (s, 3H), 2.50-2.38 (m, 1H), 1.53 (s, 9H), 1.25 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11]>>[CH:12]1([C:10](=[O:11])/[CH:9]=[CH:3]/[N:4]([CH3:5])[CH3:6])[CH2:14][CH2:13]1
Reactant: CC(=O)C1CC1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)C1CC1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
To N,N-dimethylformamide dimethyl acetal (9.51 ml, 71.3 mmol) was added cyclopropyl methyl ketone (3.34 ml, 35.7 mmol) and the mixture was heated to 150° C. in a sealed vessel. After 16 hours, the reaction mixture was cooled and concentrated to afford (2E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=[CH:12][C@H:11]([OH:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]Cl.[Na+].C([O-])(O)=O.[Na+]>CC(OC)(C)C.[K+].[Br-]>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=[CH:12][C:11](=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C=C[C@H](O)C1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C=CC(=O)C1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
Add 2,2,6,6-tetramethyl-1-piperidinyloxy (free radical) (TEMPO) (0.84 g, 5.3 mmol) and KBr (0.63 g, 5.3 mmol, in 2 mL of water) to a solution of (1S,3R)-1-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonyl)-3-hydroxycyclopent-4-ene (20 g, 66.8 mmol) in MTBE (200 mL). Cool the reaction mixture to 0° C. and add a solution of NaOCl (3.14%, 240 g, 100 mmol) containing NaHCO3 (8.4 g) dropwise, keeping the temperature below 5° C. Stir the reaction 1 hour at 0° C. and allow to warm to room temperature. Separate the layers and extract the aqueous layer with MTBE (2×200 mL). Wash the combined organic layers with 200 mL of 1N HCl solution containing 2.21 g of KI followed by 10% Na2SO3 solution (200 mL). Wash the organic layer with water (2×200 mL) and concentrate to dryness under vacuum. Dissolve the crude product in MTBE (60 mL) at 50° C. and crystallize by addition of heptane (200 mL) over 1 h. Cool the mixture was cooled to 0° C. over 2 hours and then filter. Wash the filter cake with 100 mL of cold heptane:MTBE (65:35) and vacuum dry to give 16.99 g (89% yield) of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24]C2CCCCO2)=[CH:19][CH:18]=1>CO>[NH2:9][C:7]1[N:8]=[C:3]([CH3:2])[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:6]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(COC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2M HCl (10 ml) was added to a stirred solution of the product from step (iv) (3.4 g) in MeOH (30 ml). The mixture was stirred at rt for 3 days then the solvent evaporated under reduced pressure. The residue was partitioned between DCM/aq NaHCO3 solution, the organics separated, dried and evaporated under reduced pressure to afford the subtitle compound, 2.38 g.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([C:12]([OH:14])=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl.[CH3:16][NH:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.C(N(CC)CC)C>[CH3:16][N:17]([CH3:18])[C:12]([CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])=[O:14]
Reactant: CNC
Reactant: O=C(O)C1Cc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 97.1 %

Procedure:
2-Oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid (8.56 g), dimethylamine hydrochloride (4.60 g), HOBt (7.18 g), WSC (11.1 g) and triethylamine (20 ml) were added to acetonitrile (400ml). The reaction mixture was stirred at room temperature for 43 hours. 10% aqueous citric acid solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were washed with IPE to give the entitled compound (9.486 g).
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:29])[CH2:27][F:28])([C@@:6]1([CH3:30])[CH2:5][C@@H:4]2[OH:31])[CH2:24][NH:23][CH2:22]3.[CH3:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=O.C(O)=O>C(#N)C.CCOC(C)=O>[CH3:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH2:35][N:23]1[CH2:24][C@:25]2([C:26](=[O:29])[CH2:27][F:28])[C@@H:21]([CH2:20][C@H:7]3[C@H:8]4[C@@:3]([F:2])([C@:16]5([CH3:17])[C:11]([C@@H:10]([F:19])[CH2:9]4)=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]5)[C@@H:4]([OH:31])[CH2:5][C@@:6]32[CH3:30])[CH2:22]1
Reactant: CC(C)(C)CC=O
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CNC[C@@]4(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cl
Solvent: CC#N
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CF)C1
Temperature: 140 °C
Yield: 27.6 %

Procedure:
In a closed vessel, compound 166 (180 mg, 0.391 mmol), 3,3-dimethylbutanal (0.196 ml, 1.565 mmol) and TEA (0.055 ml, 0.391 mmol) are dissolved in acetonitrile (4 ml). Formic acid (0.120 ml, 3.13 mmol) is added and the mixture is heated under microwave irradiation for 15 minutes at 140° C. LC-MS shows that the reaction is complete. The reaction mixture is diluted with AcOEt and the organic phase is washed with a saturated solution of NaHCO3 and with brine. The organic layer is dried over Na2SO4 and filtered. The solvent is evaporated to give an orange oil which is purified by preparative HPLC (acetonitrile/water, neutral phase) to yield the title compound (55 mg, 0.108 mmol, 27.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.N1CCCC1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:16]3[S:17][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)s1
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)s1
Yield: 70.3 %

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.2 g, 7.2 mmol) was reacted with 5-chloro-thiophene-2-carbaldehyde (1.05 g, 7.2 mmol) and pyrrolidine (0.7 g, 9.9 mmol) to give E/Z-6-chloro-3-(5-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.5 g, 71%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.C(Cl)Cl.[CH2:23](Cl)[O:24][CH2:25][CH2:26][O:27][CH3:28]>O.CCCCCC.C(OCC)(=O)C>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COCCOCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
In a 50 mL, 3-neck RBF equipped with a magnetic stirrer, reflux condenser, calcium chloride guard tube and thermometer pocket were sequentially charged 4-nitrophenol (1.50 g), DIPEA (2.90 mL) and DCM (25 mL). MEM-Cl (2.016 g) was added drop wise to the reaction at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then allowed to stir at room temperature for 4 hours. The reaction was monitored on TLC using hexane:ethyl acetate (8:2) as mobile phase. After completion, the reaction was poured into water and the product was extracted in ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give 2.35 g of 1-[(2-methoxyethoxy)methoxy]-4-nitrobenzene as a solid, which was used in the next step without further purification.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[C:31]([C:36]4[N:37]=[C:38]([C@@H:41]6[CH2:46][C@@H:45]7[C@@H:43]([CH2:44]7)[N:42]6C(OC(C)(C)C)=O)[NH:39][CH:40]=4)[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)[N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1.CO.C(Cl)Cl>[ClH:1].[C@@H:43]12[CH2:44][C@@H:45]1[CH2:46][C@@H:41]([C:38]1[NH:39][CH:40]=[C:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([C:23]5[CH:24]=[CH:25][C:20]([C:18]6[N:19]=[C:15]([C@@H:14]7[CH2:13][C@@H:12]8[C@@H:10]([CH2:11]8)[NH:9]7)[NH:16][CH:17]=6)=[CH:21][CH:22]=5)[CH:27]=4)[N:32]=3)[N:37]=1)[NH:42]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc(-c3ccc4nc(-c5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)n5)ccc4c3)cc2)c[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)ccc1-c1ccc2nc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.7 %

Procedure:
A solution of 4M HCl (1 mL, 4.00 mmol) in dioxane was added to a suspension of tert-butyl (1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (130 mg, 0.186 mmol) in dioxane (3 mL), MeOH (0.5 mL) and DCM (3 mL) and the mixture was stirred at rt for 2 h. The reaction was concentrated to yield an HCl salt of 2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)quinoline (140 mg) as yellow solid. LC-MS retention time 2.063 min; m/z 500.37 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 9.09 (d, J=9.0 Hz, 1H), 8.66 (s, 1H), 8.56-8.62 (m, 2H), 8.47-8.53 (m, 2H), 8.07 (s, 1H), 8.02-8.06 (m, 4H), 4.97 (dd, J=10.8, 8.0 Hz, 1H), 3.65-3.71 (m, 1H), 3.55-3.65 (m, 2H), 2.73-2.86 (m, 3H), 2.61-2.72 (m, 1H), 2.07-2.20 (m, 2H), 1.25-1.35 (m, 2H), 1.07 (t, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].O1CCOCC1.[OH-].[Na+].Cl>O>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCc1nc(Cl)c(CC(=O)O)c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
128 mg of the product of Example 16 were introduced into 2.56 ml of dioxane and 0.52 ml of 2N sodium hydroxide and the mixture was stirred at ambient temperature for 16 hours, then diluted with 10 ml of water, neutralized with 0.52 ml of 2N hydrochloric acid and evaporated to dryness under reduced pressure to obtain 135 mg of crude product which was crystallized from ethyl acetate and hexane to obtain 85 mg of the expected product melting at 180° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19]([CH3:25])([CH3:24])[CH2:18][C:17]3([CH3:27])[CH3:26])=[CH:8][C:7]=1[F:28])C.CO.[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[F:28][C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19]([CH3:25])([CH3:24])[CH2:18][C:17]3([CH3:26])[CH3:27])[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)ccc2O1

Procedure:
Following general procedure L and using [2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid ethyl ester (Compound 31, 0.2 1 g, 0.58 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by flash column chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in hexane, the title compound was obtained as a solid (0.184 g, 93%).
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH:8]=[CH:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.[Li].Cl[Si:15]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1>[CH3:20][C:19]([NH:18][Si:15]([CH3:17])([CH3:16])[CH:7]1[C:6]2[C:10](=[CH:11][C:12]3[CH2:1][CH2:2][CH2:3][C:4]=3[CH:5]=2)[CH:9]=[CH:8]1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: C1=Cc2cc3c(cc2C1)CCC3
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=Cc2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
1,2,3,5-Tetrahydro-s-indacene, lithium salt (1.790 g, 11.04 mmol) in THF (25 mL) was added drop wise to a solution of ClSi(CH3)2-NH-tBu (2.157 g, 16.56 mol) in THF (50 mL). This mixture was then allowed to stir at room temperature overnight. After the reaction period the volatile materials were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a yellow oil (2.799 g, 88.8% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccccc2Br)cc1
Temperature: 150 °C
Yield: 37.5 %

Procedure:
To a mixture of 4-fluorobenzaldehyde (2.5 g, 20.2 mmol), 2-bromophenol (3.5 g, 20.2 mmol) and potassium carbonate (3.35 g, 24.3 mmol) is added N,N-dimethylacetamide (20 mL) and the resulting reaction mixture is heated to 150° C. for 12 hours. Once complete, the reaction is cooled to room temperature and diluted with water prior to being extracted with ethyl acetate. The combined extracts are washed with brine and dried over sodium sulfate and concentrated. The resulting yellow oil is purified by column chromatography (5% ethyl acetate in hexanes) to afford 2.1 g of 4-(2-bromophenoxy)benzaldehyde.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH2:14]>P(=O)(O)(O)O.[Cl-].[Na+].O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[Br:12]
Reactant: Nc1cc(Br)c2ncc(Br)cc2c1
Reactant: O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: Oc1cc(Br)c2ncc(Br)cc2c1
Temperature: 180 °C

Procedure:
6-Amino-3,8-dibromoquinoline (1.1 g) was suspended in phosphoric acid (10 ml) containing water (10 ml) and heated in a sealed glass tube at 180° C. for 4 days. The mixture was cooled to ambient temperature, poured into brine and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate, evaporated under reduced pressure and the residual solid fractionated by chromatography (silica; hexane/ethyl acetate) to give 3,8-dibromo-6-hydroxy-quinoline, 0.4 g, as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].CO.ClCCl>ClCCCl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:29]([N:18]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)[CH:8]=1)=[O:36])[CH3:35]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1Nc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(c1ccc(F)cc1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of ethyl 5-(4-fluorobenzyl)-3-[(4-fluorophenyl)amino]pyridine-2-carboxylate (456 mg, 1.24 mmol) in 1,2-dichloroethane was added ethyl 3-chloro-3-oxopropanoate (0.18 mL, 2.36 mmol) and the resulting yellow solution was refluxed for 1 hour or until determined complete by TLC (5% methanol/dichloromethane). The mixture was cooled to ambient temperature, quenched with water and extracted with dichloromethane. The organics were washed with saturated aqueous sodium bicarbonate, brine, and dried over sodium sulfate to yield ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](4-fluorophenyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (477 mg, 80% yield) as mixture of rotamers. The yellow oil can be carried on without further purification or purified by silica gel chromatography (0-12% methanol/dichloromethane gradient elution). Spectral data was consistent with the expected product as mixture of rotamers. MS m/z 505 (M+23).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6](N(OC(C)C(O)C)OC(C)C(O)C)=[C:5](CCC)[CH:4]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)(Cl)=O)C=CC=CC=1.[CH2:50]([O:54][CH2:55][CH:56]1[CH2:63][N:62]([C:64]2[CH:69]=[CH:68][C:67]([O:70][CH2:71]CCCCCCCCCCC)=[CH:66][CH:65]=2)[CH2:61][CH:60]([CH2:83][O:84][CH2:85][CH2:86][CH2:87][CH3:88])[O:59][P:58](=[O:95])(C2C=CC=CC=2)[O:57]1)[CH2:51][CH2:52][CH3:53]>ClCCl>[CH2:50]([O:54][CH2:55][CH:56]1[CH2:63][N:62]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH3:71])=[CH:68][CH:69]=2)[CH2:61][CH:60]([CH2:83][O:84][CH2:85][CH2:86][CH2:87][CH3:88])[O:59][P:58](=[O:95])([O:2][C:3]2[CH:21]=[CH:20][CH:6]=[CH:5][CH:4]=2)[O:57]1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCc1cc(OC)ccc1N(OC(C)C(C)O)OC(C)C(C)O
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CN(C)c1ccccn1
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOCC1CN(c2ccc(OC)cc2)CC(COCCCC)OP(=O)(Oc2ccccc2)O1
Yield: 16 %

Procedure:
It is prepared from 4-methoxy-N,N-di(2-hydroxy-3-butoxy)-propyl aniline (1.91 g, 5 mmol), pyridine (1,2 g, 15 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonic dichloride (1.1 g, 5.1 mmol) in dichloromethane as described for compound 200 to obtain a pale yellow liquid 0.4 g (16%) and its isomer 0.5 g (19% a pale yellow liquid).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[CH3:24][N:25](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:24]#[N:25])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C#N)cc3C)c(C)nc12
Yield: 91 %

Procedure:
A solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.28 mmol), DMF (5 mL), and Zn(CN)2 (0.090 g, 0.76 mmol) is degassed with nitrogen for 15 minutes. Pd(PPh3)4 (0.74 g, 0.064 mmol) and the solution heated at 100° C. overnight. The solution is diluted with EtOAc (50 mL), washed with 2 M NH4OH (2×30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. Purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.39 g, 1.15 mmol, 91%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.15 (s, 3H), 2.46 (s, 3H), 2.51 (s, 3H), 3.26-3.34 (m, 1H), 6.72 (s, 1H), 7.53 (s, 1H). LC/MS (m/z): calcd. for C19H22N4S (M+H)+: 339.6; found: 339.2.