Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].B(F)(F)F>C([O-])([O-])=O.[Na+].[Na+]>[C:11]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][CH:2]([CH3:1])[O:6][C:5]=2[CH:7]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Oc2ccccc2O1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1ccc2c(c1)OC(C)O2

Procedure:
The synthesis of 2-methyl-1,3-benzodioxole is conducted by the procedure of Nichols and Kostuba (J. Med. Chem 22:1264 (1979)). A solution of 10.3 g (76 mmol) of 2-methyl-1,3-benzodioxole and 21 ml of acetic anhydride is treated with 3.5 ml BF3 etherate at 0° C. for 24 hr and at -20° C. for three days. The reaction solution is poured into 250 ml 1M Na2CO3 and extracted with ether. The ether is dried over Na2SO4, then removed under reduced pressure. Purification and distillation under reduced pressure yields the ketone, 5-acetyl-2-methyl-1,3-benzodioxole.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](Cl)(=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:1]([NH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(=O)Cl
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)CCCCCC

Procedure:
Octylamine was acrylated with one equivalent of heptanoyl chloride to provide N-octylhexanecarboxamide. The amide was reduced by reaction with diborane in tetrahydrofuran to provide N-heptyloctylamine. To a cold stirred solution of 19.79 g. of N-heptyloctylamine and 23.4 g. of sodium carbonate in 82 ml. of acetone and 82 ml. of water was added dropwise over thirty minutes a solution of 13.7 ml. of acetyl chloride in 164 ml. of acetone. The reaction mixture was stirred for twelve hours following complete addition, after which time the solvent was removed by evaporation under reduced pressure. The residual oil was dissolved in diethyl ether and washed with water and with 2 N hydrochloric acid. The ethereal solution then was dried and the solvent was removed by evaporation to provide 22.48 g. of N-heptyl-N-octylacetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3,3-bis(4-fluorophenyl)propanoate, prepared in the previous step, in THF (75 mL) at −78° C. was added LAH (1 M in PhMe, 35 mL, 35.0 mmol). The reaction mixture was warmed to 0° C. over 15 min, quenched with 6 mL of water, 12 mL of 2.5 M NaOH, followed by 18 mL of water. The mixture was stirred at room temperature for 30 min. The solids were removed by filtration and the solution was concentrated to provide 3,3-bis(4-fluorophenyl)propan-1-ol which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[C:30]([F:43])[CH:29]=2)=[O:26])[CH2:23][CH2:22]1>>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:3][C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH:27][C:25]([NH:24][CH:21]4[CH2:23][CH2:22]4)=[O:26])=[CH:29][C:30]=3[F:43])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Product: CC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 4 %

Procedure:
Method as example 143 using (S)-1-(2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 24) (212 mg, 0.5 mmol) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (182 mg, 0.57 mmol) as starting materials. Reaction mixture was partitioned between EtOAc (50 ml) and water (35 ml), the organic layer passed through a hydrophobic frit and concentrated in vacuo to leave a purple solid. The solid was purified by prep. HPLC at high pH to afford a brown/red solid which was re-purified by prep. HPLC at low pH to afford a yellow solid (9 mg, 4%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[N:31]3)=[C:26]([F:36])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:36][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[C:18]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=2)[CH:29]=[CH:28][C:27]=1[N:30]1[CH:34]=[N:33][C:32]([CH3:35])=[N:31]1
Reactant: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OC(F)(F)F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(OC(F)(F)F)cc3)cc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (3.07 g, 5.85 mmol), sodium iodide (4.38 g, 29.3 mmol), and diisoproplylethylamine (5.11 mL, 29.3 mmol) in acetone (100 mL) was heated in a sealed vessel at 100° C. for 12 h. The reaction was concentrated in vacuo. Water (250 mL) was added and the mixture was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. Ethanol (50 mL) was added to the residue. The mixture was stirred at rt for 30 min. The solid was collected by vacuum filtration to afford 630 mg (21% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 488.5. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=2.4 Hz, 1 H), 7.68 (dd, J=14.0, 2.4 Hz, 1 H), 7.61 (t, J=8.5 Hz, 1 H), 7.17-7.26 (m, 4H), 7.02 (dd, J=89, 2.4 Hz, 1 H), 6.78 (s, 1H), 4.31 (dd, J=8.5, 2.4 Hz, 1 H), 4.26 (t, J=4.9 Hz, 2 H), 2.50 (s, 3 H), 2.17-2.29 (m, 1H), 2.06-2.16 (m, 1H), 1.86-2.03 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:26](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OC(C)C)(C)C.ClCCl.C(OCC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][N:15]([CH3:26])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CN1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To dichloromethane (5 ml) were added 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (100 mg, 0.245 mmol), triethylamine (0.070 ml, 0.50 mmol) and a 37% aqueous formaldehyde solution (0.060 ml, 0.739 mmol), followed by the addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol) at room temperature. After stirring at room temperature for 14 hours, a 1N aqueous sodium hydroxide solution (6.0 ml) was added. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added diethyl ether and the mixture was washed with a 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give a white solid. The solid thus obtained was washed with diisopropyl ether, whereby the title compound (70 mg, 0.18 mmol, 74%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH2:14]C)[CH:5]([OH:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])C=C.[CH3:16]C(CC=C)C(=O)C>>[OH:11][C:5]([CH3:16])([CH:4]([CH3:1])[CH2:12][CH:13]=[CH2:14])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCC(CCCC)C(O)CC(=O)OC
Reactant: C=CCC(C)C(C)=O
Product: C=CCC(C)C(C)(O)CC(=O)OC

Procedure:
The compound of interest (11.7 g, 60%) was obtained as an oil substance (diastereomeric mixture) in the same way as in paragraph (10-a) using 3-methyl-5-hexen-2-one (17 g, 106 mmol).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=1[CH2:48][CH2:49][CH3:50]>CS(C)=O.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=3[CH2:48][CH2:49][CH3:50])[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Reactant: CCCc1cc(C(=O)OC)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OC)ccc1CC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 0.531 g (1.47 mmol) of the product of Example 1 dissolved in 2.0 mL of DMSO was added 4.40 mL of a 1.0M solution of lithium bis(trimethylsilyl)amide in THF under a nitrogen atmosphere at a temperature just warm enough to prevent the DMSO from solidifying (approximately 18° C.). During the addition of the base, the reaction mixture was further cooled to 0°-50° C. with an ice-water bath. When the addition was complete, the reaction mixture was stirred for 1 hour at 0°-5° C., then a solution of 0.496 g (1.84 mmol) of the product of Step E dissolved in 2.0 mL of THF was added via syringe. The ice-water bath was then removed and the reaction mixture was stirred at room temperature for an additional hour. The mixture was next partitioned between EtOAc and 10% aqueous NaHSO4, and extracted. The organic layer was separated, washed with saturated brine, dried (MgSO4), filtered, and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with 1% MeOH--CHCl3. After evaporation of the product containing fractions the residue was rechromatographed on a silica gel flash chromatography column eluted with 5% EtOAc--CHCl3. Evaporation of the product containing fractions and drying in vacuo afforded 0.284 (36%) of the title compound as an amorphous white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C@H:8]([CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C2CCCCO2)[CH:18]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])=[N+:2]=[N-:3].Cl>CO>[N:1]([CH2:4][C:5]([NH:7][C@H:8]([CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@@H](CSCc1cccc(OC2CCCCO2)c1)NC(=O)CN=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@@H](CSCc1cccc(O)c1)NC(=O)CN=[N+]=[N-]
Reaction time: 2.5 h
Yield: 92.1 %

Procedure:
To a 250 mL round bottom flask containing 132 (6.5 g, 15.4 mmol) in MeOH (150 mL) at RT, was added Conc. HCl (1 mL) and stirred for 2.5 h. The reaction was concentrated on silica and purified over silica gel using EtOAc:Hexanes (1:1) as an eluent to afford 133 (4.8 g, 92%) as a colorless oil.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.[H-].[Na+].O>CS(C)=O.CN(C)C=O.CO.C(O)(=O)C>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2
Reactant: O=Cc1cccc(F)c1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3c(=Cc3cccc(F)c3)c2n2ccnc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
To a suspension, maintained under a nitrogen atmosphere and at a temperature in the region of 20° C., of 2.2 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 45 ml of anhydrous dimethyl sulphoxide are added 1.34 g of 3-fluorobenzaldehyde and then, over 5 minutes, 0.72 g of 80% sodium hydride. The mixture is stirred for 15 hours at the same temperature, followed by slow addition of 45 ml of distilled water and 12 ml of acetic acid. The insoluble product formed is isolated by filtration, washed with distilled water and air-dried. The product obtained (2.6 g) is chromatographed on a column of neutral silica gel, eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are concentrated to dryness and the product obtained (1.6 g) is dissolved in 100 ml of dimethylformamide at 100° C. 30 ml of distilled water are then added and the solution is cooled to a temperature in the region of 20° C. The insoluble product formed is isolated by filtration, washed 3 times with 15 ml in total of distilled water and air-dried. The product obtained (0.86 g) is stirred in suspension in 20 ml of boiling methanol and, after cooling, is isolated by filtration, washed with 5 ml of methanol and air-dried. The product obtained (0.56 g) is dissolved in a boiling mixture of 30 ml of acetic acid and 40 ml of dimethylformamide and, after cooling to a temperature in the region of 5° C., the insoluble product formed is isolated by filtration, washed twice with 10 ml in total of acetic acid and twice with 10 ml in total of isopropyl ether, and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. 0.39 g of 10-(3-fluorobenzylidene)-5H,10H-imidazo[1,2-a]indeno-(1,2-e]pyrazin-4-one is thus obtained, melting at 360° C. (decomposition) (Analysis, % calculated C: 72.94, H: 3.67, F: 5.77, N: 12.76, O: 4.86, % found C: 73.1, H: 3.0, N: 12.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]1([CH2:21][C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:22]([CH3:23])([OH:24])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(Cl)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1-chloro-4-ethynylbenzene (3C) (1.75 mL, 12.81 mmol) in THF (40 mL) at 0° C. was added n-butyllithium (2.5 M in hexanes, 5.13 mL, 12.81 mmol) and stirred for 1 h. A solution of 1-phenylpropan-2-one (3B) (1.38 g, 10.25 mmol) in THF (5 mL) was added and the reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched with saturated NH4Cl solution and extracted with diethyl ether (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 3D as a yellow oil (2.29 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.35-7.20 (m, 9H), 3.0 (AB quart, J=13.2, 9.9 Hz, 2H), 1.59 (s, 3 H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Si:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[C:2]1[C:15]2[C:10]([C:9]([Si:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]3[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: Brc1c2ccccc2c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)c2c3ccccc3c(-c3ccc4ccccc4c3)c3ccccc23)cc1

Procedure:
9-bromo-10-triphenysilyl anthracene (4 g, 7.8 mmol), 2-naphthylboronic acid (1.6 g, 9.4 mmol) and K2CO3 (1.5 g,15.6 mmol) were dissolved in the solvent mixture of 50 mL ethylene glycol dimethyl ether and 75 mL water. The stirred solution was added tetrakis (triphenylphosphine) palladium (0) and the mixture refluxed under N2 for 16 hours. The reaction mixture was cooled and the water extracted with acetyl acetate three times. The combined organic phase was washed with portions of brine. The organic layer was then dried with MgSO4, filtered, and evaporated of solvent. The crude material was purified by column chromatography (n-hexane/acetyl acetate=10/1) to give 9-(2-naphthyl)-10-triphenysilyl anthracene (Compound 2), the reaction was following:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl.Cl[C:18]([C:20]1[CH:21]=[C:22]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:23]2[C:27]=1[CH2:26][S:25][CH2:24]2)=[O:19].C>C(Cl)Cl.C(O)CCC>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:18]([C:20]2[CH:21]=[C:22]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:23]3[C:27]=2[CH2:26][S:25][CH2:24]3)=[O:19])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CSC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1cc(-c2cccnc2)n2c1CSC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A solution of 3-aminomethylpyridine (5.5 g) and of triethylamine (10.1 g) in methylene chloride (100 cc) is added over 15 minutes at a temperature between 20° and 30° C. to a suspension of 7-chloroformyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (15 g) in methylene chloride (250 cc). The solution obtained is stirred at a temperature of about 20° C. for 16 hours. A product precipitates out. The crystals which have appeared are separated off by filtration, washed 3 times with methylene chloride (300 cc in total) and 3 times with isopropyl ether (200 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. A crude product (11.3 g) melting at 206° C. is thus obtained. This product is dissolved in boiling 1-butanol (160 cc). The solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 2 hours. The crystals which have appeared are separated off by filtration, washed 4 times with 1-butanol (100 cc in total) and 4 times with diethyl ether (100 cc in total) and are then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-(3-pyridylmethyl)-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (9.9 g) is thus obtained in the form of cream crystals melting at 210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:17])[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:9]2[C:10](=[O:16])/[C:11](=[CH:34]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)/[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([Cl:8])[CH:7]=1
Reactant: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)CC1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)/C(=C/c2ccccn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
To a stirred solution of 2-(4-bromo-2,6-dichloro-phenyl)-3-methoxy-cyclopent-2-en-1-one (0.86 g, 2.56 mmol) in anhydrous tetrahydrofuran (17 ml) at 0°C. under an nitrogen atmosphere was added dropwise potassium hexamethyldisilazide (2.81 ml of a 1.0M solution in tetrahydrofuran, 2.81 mmol) over 10 minutes followed by dropwise addition of a solution of pyridine-2-carbaldehyde (0.268 ml, 2.81 mmol) in tetrahydrofuran (1 ml) over 5 minutes. The reaction was stirred at 0°C. for 10 minutes and then allowed to warm to room temperature over 1.5 hours. The reaction was quenched with saturated aqueous NH4Cl (25 ml) and extracted with EtOAc (3×25 ml). The combined organic extracts were washed with brine (15 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product (250 mg, 20%). 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (d, 1H), 7.70 (dd, 1H), 7.55 (s, 2H), 7.45 (d, 1H), 7.40 (s, 1H), 7.25-7.20 (m, 1H), 4.05 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C[O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[C:22]=1[OH:35].Cl>O1CCCC1.O>[OH:35][C:22]1[C:21]([C:20](=[O:19])[CH2:2][C:1]([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[O:3])=[CH:26][CH:25]=[CH:24][C:23]=1[O:27][S:28]([C:31]([F:34])([F:32])[F:33])(=[O:30])=[O:29]
Reactant: CC(=O)N1CCOCC1
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)N1CCOCC1)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Reaction time: 1 h

Procedure:
A solution of N-acetylmorpholine (1.72 g, 13.3 mmol, 2 eq) in 30 ml dry tetrahydrofuran under nitrogen was cooled in an acetone/dry ice bath (−78° C.) and treated with LDA (10 ml, 2M solution in THF, 3 eq). The reaction mixture was stirred for 60 minutes then 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoic acid methyl ester [α] (2 g, 6.6 mmol, 1 eq as a solution in 10 ml dry THF) was added. The reaction mixture was allowed to warm from −78° C. to room temperature and stirred over night. The reaction was diluted with water (4 ml) followed by 2M hydrochloric acid (40 ml), then extracted three times with dichloromethane. The extracts were combined, washed with brine, dried with magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography eluting with ethyl acetate to afford trifluoro-methanesulfonic acid 2-hydroxy-3-(3-morpholin-4-yl-3-oxo-propionyl)-phenyl ester [D]. Yield 1.06 g, 40%
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]4)[C:20]3=[O:32])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[Cl:33][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:25][CH2:26][C:27]([F:31])([F:30])[CH2:28][CH2:29]2)[C:20]1=[O:32]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Yield: 100.5 %

Procedure:
Treat a solution of 3′,5′-Dichloro-4′-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (Preparation 14) (1.0 g, 2.0 mmol) in THF/water (15 mL/5 mL) with 2M aqueous LiOH (3.0 mL). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.97 g (100%) of desired product. MS (m/e): 482 (M+1).