Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH:3]=2)[N:8]=1
Reactant: Fc1cc(Br)cc2cnc(Cl)nc12
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cc(F)c3nc(Cl)ncc3c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 6-bromo-2-chloro-8-fluoroquinazoline (4.0 g, 15.4 mmol), 3,5-dimethoxyphenylboronic acid (4.47 g, 16.9 mmol), cesium carbonate (10.0 g, 30.8 mmol) and Pd(PPh3)2Cl2 (236 mg, 0.77 mmol) in THF (200 mL) and water (10 mL) was degassed with nitrogen three times, and stirred at 80° C. for 3 h. Both TLC and LCMS showed the reaction was completed. The reaction mixture was cooled to RT and directly concentrated. The residue was purified by silica gel chromatography (petroleum ether:dichloromethane=2:1 to 1:1) to afford the title compound (2.5 g, 51%) as a yellow solid. MS (ES+) C16H12ClFN2O2 requires: 318/320. Found: 319/321 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([Cl:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[Cl:14]/[CH:15]=[CH:16]/[CH2:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].ClCCl>CS(C)=O>[Cl:12][C:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:18]([CH2:17]/[CH:16]=[CH:15]/[Cl:14])[CH3:19])[C:8]=2[S:9][CH:10]=1
Reactant: CNC/C=C/Cl
Reactant: Clc1csc2c(CBr)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 2.62 g-(10 mmol) of 7-bromomethyl-3-chlorobezo[b]thiophene in 10 ml of dimethyl sulfoxide were added 1.7 g (12 mmol) of (E)-N-(3-chloro-2-propenyl)methylamine hydrochloride and 2.07 g (15 mmol) of ground potassium carbonate. The mixture was stirred for 16 hours at room temperature, and poured into 150 ml of dichloromethane. The organic layer was washed with 100 ml ×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-heptane). The desired fractions were put together and concentrated under reduced pressure to obtain 2.12 g (yield: 74%) of the above identified compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]2C(O)=O)#[N:2].O>CN1C(=O)CCC1>[F:15][C:12]([F:13])([F:14])[C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 135 °C
Reaction time: 0.67 h
Yield: 82.2 %

Procedure:
5-cyano-2-(trifluoromethyl)-1H-indole-3-carboxylic acid (Intermediate 36 2.09 g) was dissolved in NMP (10 mL) and H2O (1 mL) was then added. The mixture was heated to 130-140° C. overnight under nitrogen. The solution was cooled to room temperature and H2O (30 mL) was added and the solution stirred for 40 min. and then filtered. The cake was washed with H2O. The product is then dried under vacuum at 40° C. to give the title compound (1.42 g);
Reaction SMILES: C(O[C:4]([C:6]1[N:7](C)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=O)C.C[N:18]([CH3:20])O.[C:21]1(C)C=CC=CC=1>>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:4][NH:18][CH2:20][CH3:21])=[CH:14]2
Reactant: Cc1ccccc1
Reactant: CN(C)O
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Product: CCNCc1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 5-chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester (1.27 g, 5.3 mmol) in toluene (10 mL) was added ON-dimethyl-hydroxylamine (9.6 mL of a 1 M solution in toluene, 9.6 mmol). The resulting mixture was heated to reflux overnight after which the reaction was cooled to room temperature and quenched by the addition of 10% aqueous K2CO3 (50 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (2.12 g, 96%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.27 (m, 2H), 6.73 (s, 1H), 6.13 (s, 1H), 4.03 (s, 3H), 3.01 (d, J=4.9 Hz, 3H); MS (ESI) m/e 222 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25].[OH-:26].[Na+]>CO.O.Cl>[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:2]([NH:3][C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25])=[O:1])([OH:26])=[O:11]
Reactant: [OH-]
Reactant: O=C(O)c1cccc2c1OB(O)[C@@H](N1C(=O)c3ccccc3C1=O)C2
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1C(=O)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 mg of (R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid in a mixture of methanol and H2O (2 mL, 1:1) was added 1 N NaOH (0.5 mL) and the resulting reaction mixture was stirred at room temperature for 3 hr. IN HCl was added to adjust the pH of the solution to 3. The product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 356 (MH)+.
Reaction SMILES: [Cl:1][C:2]1N=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[C:5]([F:20])=[CH:4][N:3]=1.ClC1N=C(Cl)[C:25](F)=[CH:24]N=1.[CH2:30](OC1C=CC(N)=CC=1)CCCCC>>[Cl:1][C:2]1[CH:30]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH3:25])=[CH:11][CH:10]=2)[C:5]([F:20])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCCCOc1ccc(N)cc1
Reactant: CCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Product: CCCCCCOc1ccc(Nc2cc(Cl)ncc2F)cc1

Procedure:
In like manner to the preparartion of 2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-n-hexyloxyaniline gave 2-chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyridineamine. The crude product was purified by chromatography (4:1 CHCl3/EtOAc) to afford (14) (0.74 g, 76%) as a red-brown oil that solidified upon standing: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=2.7 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.84 (bs, 1H), 3.96 (t, J=6.5 Hz, 2H), 1.83-1.74 (m, 2H), 1.48-1.41 (m, 2H), 1.36-1.34 (m, 4H), 0.93-0.89 (m, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[C:36]([C:40]1[CH:45]=[CH:44][N:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:42]4[CH:41]=[C:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:45]=[CH:44][N:43]=4)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In a round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (95 mg, 0.17 mmol) and 4-tert-butyl-2-(tributylstannyl)pyridine (141 mg, 0.20 mmol) were dissolved in DMF (1.6 mL). The reaction mixture was evacuated and backfilled with Argon. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and copper (I) iodide (7 mg, 0.037 mmol) were added. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, quenched with 5 mL water and extracted with 50 mL diethyl ether (2×). The combined organic layers were washed twice with 5 mL water and once with 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g SiO2 with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-2% MeOH). All fractions containing product were combined and concentrated to provide 68 mg (59%) of 2-(4-tert-butyl-pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH2:36][CH3:37]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:35][CH2:36][CH3:37])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: CCCI
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 48.4 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)benzyl]xanthine (657 mg), potassium carbonate (242 mg) and propyl iodide (427 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate =1:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (352 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([CH2:10][CH2:11]O)[CH2:2]1.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].CS(Cl)(=O)=O.[Br-:29].[Li+]>O1CCCC1>[Br:29][CH2:11][CH2:10][C@H:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:20](=[O:22])[CH3:21])[CH2:2]1
Reactant: [Br-]
Reactant: OCC[C@@H]1CNc2ccccc21
Reactant: CC(=O)Cl
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1C[C@@H](CCBr)c2ccccc21
Temperature: -21.5 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a cooled (−28° C.) solution of (S)-2-(2,3-dihydro-1H-indol-3-yl)ethanol (8.5 g, 0.052 mol) in tetrahydrofuran (500 mL) and triethylamine (5.6 g, 0.055 mol) was added a solution of acetyl chloride (4.0 g, 0.051 mol) in tetrahydrofuran (200 mL) over a period of 35 min at −35 to −30° C. The mixture was stirred at −25 to −18° C. for 20 min, and an additional amount of triethylamine (6.3 g, 0.062 mol) was added followed by a solution of methanesulfonyl chloride (6 g, 0.052 mol) in tetrahydrofuran (200 mL) over a period of 25 min at −12 to −3° C. The resulting mixture was filtered and concentrated in vacuo. The residue was dissolved in acetone (600 mL) and lithium bromide (21.7 g, 0.25 mol) was added. The mixture was boiled under reflux for 1 h, filtered and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 1:1) to give the title compound (10.6 g, 76%).
Reaction SMILES: C([O:3][P:4]([CH2:7][C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]2=[O:33])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([OH:6])=[O:5])C.C(N([CH2:39][CH3:40])CC)C.[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].CN(C1C=CC=CN=1)C>CN(C=O)C>[C:41]([O:47][CH2:48][C:7]([CH2:39][CH3:40])([P:4]([OH:6])([OH:3])=[O:5])[C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]2=[O:33])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(O)OCC)CCCC2)CCc2ccccc21
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)C2(C(CC)(COC(=O)C(C)(C)C)P(=O)(O)O)CCCC2)CCc2ccccc21
Reaction time: 8 h

Procedure:
0.6 g of ethyl (3S)-3-(1-ethylphosphonomethyl-cyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 5) was dissolved in 20 ml of DMF with exclusion of moisture and then treated with 1.86 ml of triethylamine, 0.88 ml of pivaloyloxymethyl chloride and 0.1 g of dimethylaminopyridine. The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with water and then dried over sodium sulfate. Concentration in vacuo yielded a crude product which for purification was chromatographed on 50 g of silica gel (eluent: initially n-hexane/ethyl acetate 3:7, the amount of ester gradually being increased to 100%). 188 mg of the title compound were obtained as an oil, IR=1740, 1650 cm-1 (CH2Cl2); [α]D20 =-124.1° (c=0.228 in methanol).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>O>[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6]([OH:1])=[O:7]
Reactant: [OH-]
Reactant: COc1ccc(C=O)c(F)c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into a warm (55° C.) mixture of Ag2O (13.5 g, 58.4 mmol), NaOH (19.5 g, 487 mmol) and water (200 mL) was added 2-fluoro-4-methoxybenzaldehyde (15 g, 97.4 mmol). The mixture was stirred for 1 h, filtered off and the precipitated solids were washed with hot water (10 mL). The filtrate was added slowly into cold (0° C.) HCl (5N) with vigorous stirring. The precipitated solid was filtered, washed with water and dried to give a white solid (13.6 g, 82% yield, m.p. 194-196° C.); MS m/e 169 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][N:5]([CH3:7])[CH:6]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[C:3](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(C=O)n1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc(Br)c(/C=C/C(=O)O)n1

Procedure:
A solution of 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol), malonic acid (825 mg, 7.94 mmol) and piperidine (0.12 mL, 1.2 mmol) in pyridine (0.60 mL) was heated to reflux for 3 hours. The mixture was then poured into 10% HCl and extracted with ethyl acetate (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford (2E)-3-(4-bromo-1-methyl-1H-pyrazol-3-yl)prop-2-enoic acid as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (318 mg) in DMF (5 mL) was added sodium hydride (71 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-4′ fluoroacetophenone (317 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a peach colored solid.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Cl-].[CH3:12][S:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1.[F:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[C:46](=O)[CH:45]([CH3:51])[CH2:44]2>O.C1C=CC=CC=1>[F:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[C:46](=[CH:18][C:17]1[CH:16]=[CH:15][C:14]([S:13][CH3:12])=[CH:39][CH:38]=1)[CH:45]([CH3:51])[CH2:44]2
Reactant: CSc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1Cc2cc(F)ccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CSc1ccc(C=C2c3ccc(F)cc3CC2C)cc1
Temperature: 75 °C

Procedure:
169 Mg. (1.5 mm) of potassium t-butoxide was dissolved in 2 ml. of DMSO and treated with 651 mg. (1.5 mm) of p-methylthiobenzyltriphenylphosphonium chloride dissolved in 1 ml. of DMSO. To this solution was added 270 mg. (1.65 mm) of 5-fluoro-2-methyl-1-indanone in 2 ml. of DMSO. The solution was heated at 75°C for 15.5 hours. Benzene and water were added and the benzene layer was washed five times with water. The benzene layer was dried over Na2SO4 and evaporated to dryness under vacuum. The weight was 915.6 mg. This material was eluted through 8 g. of silica gel with benzene to remove triphenylphosphine oxide. The eluate weighed 372 mg. after removal of solvent. This was rechromatographed through 15 g. of silica gel using hexane and 95.9 mg. of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-indane was isolated, melting point 67° to 70°C.
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH2:30])=CC=1C(O)=O.N1CCCC1>>[N:14]1([C:8]2[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH2:30])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: NS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 19 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J. Indian Chem. Soc.; 16; 1939; 100, 106) and pyrrolidine and obtained in 19% yield. MS (m/e): 269.4 (MH− 100%).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH:8]1([C:18]([OH:20])=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9]1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1>ClCCl>[CH:8]1([C:18]([N:3]2[CH2:4][CH2:5][C:14]3([NH:30][C:31]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:28]4[CH:10]=[CH:11][CH:12]=[C:13]34)[CH2:7][CH2:6]2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9]1
Reactant: CCN(CC)CC
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)C1OCCc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(C1OCCc2ccccc21)N1CCC2(CC1)Nc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,5-dihydropyrrolo[1,2-a]quinoxaline-spiro-4-piperidine (2.0 mmol), triethylamine (2 mmol), isochroman-1-carboxylic acid (2 mmol) and Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 hours. The mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL), stirred for 2 hours, and the product was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated at reduced pressure to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded isochroman-1-yl(5′H-spiro[piperidine-4,4′-pyrrolo[1,2-a]quinoxaline]-1-yl)methanone. 1H NMR (300 MHz, CDCl3/TMS) δ 7.31-7.05 (m, 6H), 6.96 (dd, J=13.6, 6.1 Hz, 1H), 6.87-6.71 (m, 2H), 6.30 (t, J=3.1 Hz, 0.5H), 6.25 (t, J=3.1 Hz, 0.5H), 6.07 (d, J=2.1 Hz, 0.5H), 5.88 (d, J=2.1 Hz, 0.5H), 5.52 (s, 1H), 4.28-4.03 (m, 3H), 3.91-3.68 (m, 2H), 3.48-3.12 (m, 2H), 3.10-2.96 (m, 1H), 2.12-1.78 (m, 2.5H), 1.68-1.54 (m, 2H), 1.44-1.36 (m, 0.5H). 13C NMR (75 MHz, CDCl3/TMS) δ 168.30, 133.82, 132.75, 132.61, 132.31, 132.18, 129.01, 127.24, 126.29, 125.68, 124.63, 119.64, 116.30, 114.50, 114.36, 109.91, 102.92, 102.61, 79.59, 79.39, 64.55, 51.36, 41.63, 41.50, 38.67, 36.30, 35.69, 35.52, 28.00.
Reaction SMILES: [O-]S([C:5](F)(F)F)(=O)=O.[OH:9][C@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C@H:18]([CH3:21])[CH:19]=[CH2:20])[O:13][C@:12]([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)([O:22][CH3:23])[CH2:11]1.O[C@H:40]1[CH2:45][C@@H:44](CCCC=C)[O:43][C@:42]([C@@H:53]2[CH2:57]SC(=O)N2CC2C=CC(OC)=CC=2)(OC)[CH2:41]1>>[CH3:5]/[C:40](/[CH2:41][CH2:42][CH:53]=[CH2:57])=[CH:45]/[C:44]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C@H:18]([CH3:21])[CH:19]=[CH2:20])[O:13][C@@:12]([O:22][CH3:23])([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:11]1)=[O:43]
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: C=C[C@@H](C)CC[C@@H]1C[C@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: C=CCC/C(C)=C\C(=O)O[C@@H]1C[C@@H](CC[C@H](C)C=C)O[C@@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)C1

Procedure:
Triflate formation using the method shown in Example 22, with the modification that (R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, followed by triflate displacement using the method shown in Example 23, afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([NH2:45])=[CH:42][CH:43]=2)[C:38](C)=[CH:37]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([NH:45][C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[N:36]([CH3:35])[CH:37]=[CH:38]2)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(C)c2ccc(N)cc12
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)Nc2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 95.3 %

Procedure:
2,4-Dibenzyloxy-5-isopropylbenzoic acid (5.64 g, 15.0 mmol, 1.00 equiv.) in 80 mL dichloromethane at room temperature was treated with oxalyl chloride (2.00 g, 15.75 mmol, 1.05 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour. Solvent and excess (COCl)2 were removed on rotary evaporator. The residue was dissolved in 100 mL dichloromethane, and treated with 1,3-dimethyl-5-aminoindole (2.40 g, 15.0 mmol, 1.00 equiv.) and triethylamine (2.28 g, 22.5 mmol, 1.50 equiv.) at 0° C. for one hour. Normal aqueous workup and removal of solvent gave a light brown solid that was washed with ether to yield 2,4-dibenzyloxy-5-isopropyl-N-(1-methyl-1H-indol-5-yl)-benzamide (A) as off-white solid (7.20 g, 14.3 mmol, 95%)