Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:9])[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[F:10][C:11]([F:46])([F:45])[C:12]1[CH:13]=[C:14]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH:27]=O)[CH2:19][C@H:18]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[ClH:1].[ClH:1].[F:46][C:11]([F:10])([F:45])[C:12]1[CH:13]=[C:14]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:4]2[CH2:5][CH2:6][O:7][CH2:8][C:3]2([CH3:9])[CH3:2])[CH2:19][C@H:18]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:16]
Reactant: CC1(C)COCCN1
Reactant: Cc1ccc(C[C@@H]2CN(CCOCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCOCCN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 1 h
Yield: 132.2 %

Procedure:
To a stirred mixture of 3,3-dimethylmorpholine hydrochloride (63 mg) and triethylamine (42 mg) in dichloromethane (5 ml) were added (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(formylmethoxy)ethyl]piperazine (200 mg) and sodium triacetoxyborohydride (120 mg) at room temperature. The resulting mixture was stirred for 1 hour and then treated with aqueous sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using dichloromethanemethanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-[2-(3,3-dimethylmorpholino)ethoxy]ethyl]piperazine dihydrochloride (193 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O[NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[NH:16].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][NH:16][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[NH:14])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)cc1Cl
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of the product of Step B (0.25 g; 1.43 mmol), and the product of Step C (0.23 g; 1.31 mmol) in anhydrous THF (5 ml), PyBroP (0.67 g; 1.44 mmol) was added followed by DIPEA (0.57 ml; 3.3 mmol), with stirring, at room temperature under N2. After 1 h of stirring, the mixture was diluted to 20 ml with EtOAc, washed with saturated NH4Cl (5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by crystallization from EtOAc/hexane to give the title compound (0.42 g; 93%), as a creamy solid. 1H-NMR (CD3OD) 3.96 (s, 3H); 5.41 (s, 1H); 6.52 (d, 1H, J=3.2 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.27 (d, 1H, J=3.2 Hz); 7.41-7.77 (m, 2H); 8.0 (s, 1H); 8.11 (dd, 1H, J=2; 8.7 Hz); 8.15 (d, 1H, J=2 Hz).
Reaction SMILES: ClC(Cl)C(O)=O.C(S)CCCCC.[CH2:14]([S:20][CH:21]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[NH2:32][C:33]1[C:42]([S:43][CH3:44])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][CH:37]=[N:38]2>>[CH2:26]([S:25][CH:21]([S:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:22]([OH:24])=[O:23])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[CH3:44][S:43][C:42]1[C:33]([NH:32][C:22](=[O:24])[CH:21]([S:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[CH:35]2
Reactant: CSc1ccc2ncccc2c1N
Agent: CCCCCCSC(SCCCCCC)C(=O)O
Agent: O=C(O)C(Cl)Cl
Solvent: CCCCCCS
Product: CCCCCCSC(SCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12

Procedure:
2,2-Di(hexylthio) acetic acid was synthesized from dichloroacetic acid and hexanethiol using a procedure similar to that described in Example 1. 2, 2-Di(hexylthio)acetic acid and 5-amino-6-methylthioquinoline were coupled to give the title compound using the procedure described in Example 25.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13].P(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: COc1cc(C=O)cc(C=O)c1O
Agent: BrP(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(C=O)c1
Temperature: 0 °C

Procedure:
To a suspension containing 1.8 g of 4-hydroxy-5-methoxyisophthalaldehyde in20 ml of dichloromethane was added 35 ml of 1 molar PBr3 in dichloromethane. The mixture was allowed to stand over night at room temperature and poured into ice-water, Dichloromethane was evaporated in vacuo. After cooling the product was filtered and washed with wash. Yield 0.94 g (57%), m.p. 192°-195° C.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:55])([CH3:54])[CH2:4][C:5]([C:7]1[CH:48]=[CH:47][C:10]([O:11][CH2:12][C:13]2[CH:46]=[CH:45][C:16]([CH2:17][NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)=[O:20])=[CH:15][CH:14]=2)=[C:9]([C:49]([F:52])([F:51])[F:50])[C:8]=1[OH:53])=[O:6]>C(O)C>[CH3:2][C:3]([CH3:55])([CH3:54])[CH2:4][C:5]([C:7]1[CH:48]=[CH:47][C:10]([O:11][CH2:12][C:13]2[CH:46]=[CH:45][C:16]([CH2:17][NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])=[CH:15][CH:14]=2)=[C:9]([C:49]([F:52])([F:51])[F:50])[C:8]=1[OH:53])=[O:6]
Reactant: CC(C)(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c(C(F)(F)F)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)c3c[nH]cn3)cc2)c(C(F)(F)F)c1O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
Add a 2.5N solution of hydrogen chloride (10 mL, 25.00 mmol) to 1-trityl-1H-imidazole-4-carboxylic acid 4-[4-(3,3-dimethyl-butyryl)-3-hydroxy-2-trifluoromethyl-phenoxymethyl]-benzylamide (217 mg, 296 μmol) in ethanol (10 mL). Stir the reaction mixture for 1.5 hr at 60° C. Cool the reaction mixture to room temperature and filter the precipitate. To the filtrate add water to precipitate the product. Filter the precipitate and triturate it with ether to remove the remaining trityl impurity. Filter the solid to give the title compound as a white solid (121 mg, 83% yield). MS (m/z): 490 (M+1).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].I[CH2:13][CH2:14][CH3:15].O>CN(C=O)C>[CH2:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:14][CH3:15]
Reactant: CCCI
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccccc1C=O
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of salicylaldehyde (12.21 g, 0.1 mol) in DMF (65 ml) was cooled in an ice/water bath under argon and 60% sodium hydride in mineral oil (4.0 g, 0.1 mol) was added in several portions. The mixture was stirred for one hour and then iodopropane (16.99 g, 0.1 mol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, poured into water (800 ml) and stirred. The mixture was extracted with chloroform (3×), the chloroform layer was concentrated in vacuo and the dark oil thus obtained was distilled under vacuum (92-94° C. at 1.15 mm Hg) to afford 12.68 g (77%) of 2-propoxybenzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-])=O.[PH2]([O-])=O.[Na+].[FH:20].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].N1C=CC=CC=1.F.N1C=CC=CC=1.O>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:20])=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=[PH2][O-]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Cc1cc(F)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The starting compound (I) in Scheme 1 is readily prepared from methyl 2-(2-nitro-4-chlorophenyl)acetate, 5% palladium on carbon, sodium hypophosphite and water, pursuant to the reactions described by Johnstone, et al., Tetrahedron 34, 213, (1978). In step [a] compound (I) is reacted with either hydrogen fluoride-pyridine or anhydrous hydrogen fluoride. In the case of hydrogen fluoride-pyridine, compound (I) is dissolved in a minimum amount of pyridine and added to an ice-bath cooled solution of the hydrogen fluoride-pyridine. After the addition, the temperature of the reaction is raised to 25° C. to 50° C. and the two reagents are allowed to react for one hour. The reaction mixture is cooled to room temperature and the pH of the mixture adjusted to 7 using a solution of weak base, preferably sodium carbonate. In the case of anhydrous hydrogen fluoride, compound (I) is cooled to -78° C. in a reaction vessel, anhydrous hydrogen fluoride is condensed into the reaction vessel and the vessel is sealed. The reaction mixture is warmed to 25° C. to 50° C. and stirred for between 3 to 4 hours. The reaction vessel is opened and excess hydrogen fluoride is aspirated off. In either case rearrangement occurs to produce methyl (2-amino-4-chloro-5-fluorophenyl)acetate (II). Compound (II) can be purified by standard techniques well known to those skilled in the art. Alternatively, compound (II) can be used directly for the next reaction step.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([CH2:21][CH3:22])[C:8]=1[C:9]([O:11]CC)=[O:10])([O:3][CH2:4][CH3:5])=[O:2]>O1CCCC1.[OH-].[Na+]>[C:1]([NH:6][C:7]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([CH2:21][CH3:22])[C:8]=1[C:9]([OH:11])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])cc(CC)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc([N+](=O)[O-])cc(CC)c1C(=O)O

Procedure:
A solution of ethyl 2-carboethoxyamino-4-nitro-6-ethyl-benzoate in tetrahydrofuran (10 ml) and sodium hydroxide (20 ml, 10%) was stirred at room temperature for 20 hours. The solution was extracted with ethyl acetate. The aqueous layer was acidified to pH=1 with 6M HCl, and then immediately extracted with ethylacetate. The ethyl acetate extract was washed with water and dried over magnesium sulphate. Solvent evaporation gave a solid which was further recrystallized from methylene chloride:petroleum ether to yield 2-carboethoxyamino-4-nitro-6-ethyl benzoic acid, m.p. 121°-123° C. as orange crystals: IR: 1665, 1720, 1620, 1510, 2500-3200(br), 3500 cm-1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]([N:32]1[CH2:35][C:34](=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][O:48][Si](C(C)(C)C)(C)C)[CH:42]=2)[S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1.C(OCC)(=O)C>[CH:19]([N:32]1[CH2:33][C:34](=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][OH:48])[CH:42]=2)[S:37]([CH3:40])(=[O:39])=[O:38])[CH2:35]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(CO)c1
Reaction time: 3 h
Yield: 57.8 %

Procedure:
4 cm3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution, cooled to 5° C., of 1.1 g 1-benzhydryl-3-([3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}azetidine in 10 cm3 of tetrahydrofuran. The mixture is stirred for 3 hours at a temperature close to 20° C. and then taken up in 100 cm3 of ethyl acetate and twice 50 cm3 of water. The organic phase is decanted off, extracted, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (95/5 by volume) as eluent and collecting 60 cm3 fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.5 g of 1-benzhydryl-3-[(3-hydroxymethylphenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a white solid melting at 152° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.50 (2H, d, J=5 Hz, OCH2), 4.75 (1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (8H, m. 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.N>O1CCCC1>[CH3:17][C:18]1[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH2:20][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCCCCC1=C(C)C(=O)CC1
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC1=CCC(c2cccc3cccnc23)=C1C
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 6.8 g (32 mmol) of 8-bromoquinoline in 90 ml of tetrahydrofuran was cooled to −90° C., and 12.8 ml of n-butyllithium (2.5 M in hexane, 32 mmol) were subsequently added while stirring. After stirring for 15 minutes at this temperature, 5.3 g (32 mmol) of 2-methyl-3-pentylcyclopent-2-enone (dihydroisojasmone) were added while stirring. The mixture was stirred at this temperature for a further one hour, allowed to warm to room temperature and then refluxed for one hour. After cooling to room temperature, a mixture of 30 g of ice and 30 g of concentrated hydrochloric acid was added and the resulting mixture was refluxed for 2 hours. The mixture was allowed to cool to room temperature while stirring and ammonia solution was added until a pH of 12 had been reached. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was dissolved in 5 ml of toluene and then admixed with 80 ml of hexane. The precipitate formed was filtered off and dried. The residue obtained in this way was distilled at >110° C. and 1×10−2 mbar to give 2.6 g of 2-methyl-3-pentyl-1-(8-quinolyl)cyclopentadiene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=O)[CH:7]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[CH2:19][CH2:20][C:21]4[C:26]3=[C:25]([CH:24]=[CH:23][CH:22]=4)[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:8][C:6]=2[CH:7]=1
Reactant: Cc1ccc(N2CCc3ccccc32)c(NC(=O)N2CCN(C)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Yield: 41 %

Procedure:
A stirred mixture of 35.1 (0.10 mole) of N-[5-methyl-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 5c in 500 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture), and then treated first with 250 ml of ice-cold 2N-NaOH, then with 500 ml of chloroform. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed thrice with water, and concentrated in vacuo to an oil. This was dissolved in 100 ml of boiling acetone, then allowed to crystallize at room temperature to afford 13.5 g (41% overall yield) of 9-methyl-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepine, m.p. 160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH2:33])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(N)=O)cc2)cc1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a 30 mL vial, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (98 mg, 0.23 mmol) was dissolved in DMF (2 mL). The vial was charged with HATU (129 mg, 0.34 mmol) and DIEA (0.119 mL, 0.68 mmol) and the mixture was stirred for 10 min. A color change from pale orange to a dark orange was observed. To the solution was added NH4Cl (24.24 mg, 0.45 mmol) and the reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. aq. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated to afford the crude product. The crude material was purified by column chromatography (SiO2, 1-10% MeOH/DCM) to afford (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (77 mg, 0.18 mmol, 79% yield) as an off white solid. 1H NMR (400 MHz, CD3OD) δ ppm=8.00 (s, 4H), 7.59-7.70 (m, 2H), 7.45-7.55 (m, 2H), 7.42 (d, J=2.02 Hz, 1H), 7.24 (d, J=8.59 Hz, 1H), 6.84-7.02 (m, 4H), 6.52 (d, J=15.66 Hz, 1H), 3.88 (s, 2H), 3.79 (s, 3H). LC/MS (m/z, MH+): 432.3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:33]=[CH2:34])=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]>C1C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:33]([C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]=1[CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate (17.7 g) and tris(triphenylphosphine)rhodium chloride (1.2 g) in benzene (180 ml) and ethanol (180 ml) was hydrogenated for 11 hours. The solvents were removed under vacuum and the residue was crystallized from ethyl acetate/tert-butyl methyl ether to afford methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate, m.p. 101.3°-102.8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]([CH3:19])[C:14](=[O:18])[CH:15]=[C:16](O)[C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:12]=2[N:13]([CH3:19])[C:14](=[O:18])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)cc(O)c2cnn(-c3cccc(F)c3)c21
Product: Cn1c(=O)cc(Cl)c2cnn(-c3cccc(F)c3)c21
Temperature: 90 °C

Procedure:
A mixture of 1-(3-fluorophenyl)-4-hydroxy-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (2.15 g, 8.27 mmol) and phosphorous oxychloride (10.0 mL, 107 mmol) was heated at 90° C. in an oil bath for 2.5 h. The excess POCl3 was removed on the rotovap and the resulting orange residue was treated with ice and solid Na2CO3 with stirring, and extracted 3×100 mL with EtOAc. The combined EtOAc layers were washed with brine, dried over MgSO4 and concentrated. Purification of the resulting crude material on an ISCO (40 g column, eluting with a gradient of 25-60% EtOAc in Hexanes) provided the title compound as a yellow crystalline solid. MS (ESI, pos.ion) m/z: 278.1 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH:7]1([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH2:16])[CH2:9][CH2:8]1.CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[CH:7]1[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C=NCCCl
Reactant: Nc1cnccc1C1CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1cnccc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
1-Chloro-2-isocyanatoethane (472 mg, 4.477 mmol) was added drop wise to a stirred mixture of 4-cyclopropylpyridin-3-amine (I-1b: 400 mg, 2.78 mmol) in toluene (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The crude product was concentrated and purified by column chromatography on silica gel (2% methanol in CHCl3) afforded 200 mg of the product (28% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:24][CH3:25])=[C:15]([CH:21]=[CH:22][CH:23]=3)[O:16][CH2:17][C:18](O)=[O:19])[N:10]([C:26](=[O:36])[C:27]3[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=3[F:35])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:61][C:56]2[CH:57]=[CH:58][CH:59]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(NC)CC1>CN(C=O)C>[CH:57]1([CH2:56][NH:61][C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:21]=[CH:22][CH:23]=[C:13]([CH:11]3[N:10]([C:26](=[O:36])[C:27]4[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=4[F:35])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:14]=2[O:24][CH3:25])[CH2:59][CH2:58]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1c(OCC(=O)O)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: CNC1CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCC(=O)NCC2CC2)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
To a solution of {3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid (0.029 mmol) in 1 mL of DMF is added DIEA (0.058 mmol), HATU (0.058 mmol) and cyclopropyl methylamine (0.058 mmol). The reaction mixture is stirred for 12 hours. The mixture is purified by preparative LC/MS (20-100% MeCN/H2O) to give N-cyclopropylmethyl-2-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetamide: 1H NMR (400 MHz, CDCl3) δ 7.55-7.51 (m, 3H), 7.12-6.99 (m, 4H), 6.9 (d, J=7.6 Hz, 2H), 6.77 (t, J=8.4 Hz, 2H), 4.56 (s, 2H), 4.08 (s, 3H), 3.26-3.2 (m, 2H), 1.02-0.99 (m, 1H), 0.57-0.52 (m, 2H), 0.25 (m, 2H); LC/MS (ES+): 574.1 (M+1)+.