Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[CH:13]([O:17][CH3:18])[O:12][C@@H:11]1[CH2:19][OH:20])(=O)C1C=CC=CC=1.CO>N>[F:16][C@@:14]1([CH3:15])[CH:13]([O:17][CH3:18])[O:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[OH:9]
Reactant: COC1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@@]1(C)F
Agent: N
Solvent: CO
Product: COC1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Yield: 70 %

Procedure:
(2R,3R,4R)-4-fluoro-2-(hydroxymethyl)-5-methoxy-4-methyl-tetrahydrofuran-3-yl benzoate (about 18 g, 63.3 mmol) in methanolic ammonia solution (25% w/w, 360 ml) was stirred at room temperature for about 36 hours, completion of the reaction monitored by thin-layer chromatography and methanol was removed under reduced pressure. Water added to the reaction mixture and extracted with ethyl acetate, the organic layer was dried over sodium sulphate and concentrated under reduced pressure. Purification by silica gel column chromatography using 20% ethyl acetate: hexane eluded the title compound (8 g) as an off-white solid. Yield: 70%; 1H NMR (300 MHz, CDCl3): δ 4.79 (d, 1H, J=10.8 Hz), 4.01-3.97 (m, 2H), 3.85 (d, 1H,), 3.71-3.66 (m, 1H), 3.44 (s, 3H), 2.05 (brs, 1H, —OH), 2.02 (brs, 1H, —OH), 1.47 (d, 3H, J=23.4 Hz); Mass: [M+Na]+: 203 (100%); IR cm−: 3437, 3372, 3294, 2924, 1459, 1102, 1049, 1006, 821, 731.
Reaction SMILES: Br[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=2[CH3:20])=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.BrC1C(Br)=CSC=1C=O.OC1C=CC(B(O)O)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([O:50][CH3:51])[CH:42]=1>CCOC(C)=O>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[C:3]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[CH3:20])=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)=[C:43]([O:50][CH3:51])[CH:42]=1
Reactant: Cc1cc(NS(C)(=O)=O)ccc1-c1c(Br)csc1C=O
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: O=Cc1scc(Br)c1Br
Agent: OB(O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1csc(C=O)c1-c1ccc(NS(C)(=O)=O)cc1C
Yield: 365.2 %

Procedure:
Followed the procedure described in General Scheme II, with modification. Step 1 was followed where the starting material was N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (Intermediate 4) instead of 3,4-dibromothiophene-2-carbaldehyde (Intermediate I), starting material 8A was 4-chloro-2-methoxyphenylboronic acid. After purification by column chromatography (PE:EtOAc=3:1) N-(4-(4-(4-chloro-2-methoxyphenyl)-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (380 mg, yield 365.2%) was obtained. Step 3 of Scheme II was then followed with column conditions (PE: EtOAc=3:1) to afford (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(2-methyl-4-(methylsulfonamido)phenyl)thiophen-2-yl)acrylate (280 mg, yield 63.4%). Step 4 of Scheme II gave 200 mg of product (yield 71%) followed by Step 5 (with purification by prep-HPLC) gave Example 10 (41.9 mg, 13% yield). 1H NMR (DMSO-d6 400 MHz): δ 9.73 (s, 1H), 7.38 (s, 1H), 6.93 (m, 4H), 6.90 (s, 1H), 6.86 (m, 1H), 3.5 (d, 3H), 2.95 (s, 1H), 2.75 (m, 2H), 7.01 (t, J=7.2 Hz, 2H), 1.82 (s, 3H); MS (ESI): m/z 502.0 [M+23]+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[C:10]2[C:11]3[O:15][CH:14]=[N:13][C:12]=3[C:16]([F:19])=[C:17]([F:18])[C:9]=2[N:8]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])C1=O)(=[O:5])=[O:4].[K].FC1C2N=COC=2C(NS(C2CC2)(=O)=O)=C(NC2C=CC(I)=CC=2F)C=1F>>[F:19][C:16]1[C:12]2[N:13]=[CH:14][O:15][C:11]=2[C:10]([NH:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:29])[CH3:1])=[C:9]([NH:8][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])[C:17]=1[F:18]
Reactant: CN(C)S(=O)(=O)n1c(=O)n(-c2ccc(Br)cc2F)c2c(F)c(F)c3ncoc3c21
Agent: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Agent: [K]
Product: CN(C)S(=O)(=O)Nc1c(Nc2ccc(Br)cc2F)c(F)c(F)c2ncoc12

Procedure:
Compound 1F was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-7-oxo-6,7-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazole-8-sulfonic acid dimethylamide (I-24a: 100 mg, 0.203 mmol) and potassium trimethylsilonolate (39 mg, 0.305 mmol) using procedures analogous to those described above for Compound 1A to afford 30 mg of the product (29% yield). H1NMR (CDCl3, 300 MHz): δ 8.14 (s, 1H), 7.11-7.24 (m, 2H), 7.12 (dt, 1H), 6.79 (s, 1H), 6.58-6.48 (m, 1H), 2.90 (s, 6H). LCMS: 95.77%, m/z=462.9 (M−2). HPLC: 96.26%
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 30.4 grams (0.116 mole) of triphenylphosphine in about 116 mL of methylene chloride is stirred, and 7.9 grams (0.116 mole) of imidazole is added. Upon completion of addition, the reaction mixture is stirred about one hour until the imidazole dissolves, then 29.4 grams (0.116 mole) iodine is added portionwise. After the iodine dissolves, the reaction mixture is cooled to 0° C., and a solution of 36.3 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol in about 77 mL of methylene chloride is added dropwise, while maintaining the reaction mixture temperature below 0° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then taken up in about 500 mL of acetonitrile and extracted with three 300 mL portions of hexane. The combined extracts are concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 17.8 grams of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 136.1 %

Procedure:
(R)-4-methyl-4-(6-(4-pentylcyclohexyloxy)naphthalen-2-yl)oxazolidin-2-one (0.3672 g, 0.0009284 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL EPA vial equipped with a stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.00 mL) was added and the mixture was heated at 80° C. overnight. TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under vacuum. The product was dissolved in methylene chloride (5 mL) and washed with water (2×5 mL). The layers were separated (phase separator cartridge) and the organic layer was concentrated to dryness and purified by HPLC to give 0.467 g of the title compound (14% yield). MS: m/z=353.36 [M−NH2]+. 1H NMR (400 MHz, MeOD) δ 0.90-0.98 (m, 3H), 1.10-1.24 (m, 1H), 1.26-1.54 (m, 8H), 1.58-1.74 (m, 2H), 1.80 (s, 3H), 1.86-1.95 (m, 2H), 2.03-2.13 (m, 2H), 2.20-2.29 (m, 2H), 3.80-3.87 (m, 1H), 3.91-3.97 (m, 1H), 4.36-4.79 (m, 1H, 1:1 ratio), 7.17-7.26 (m, 1H, 1:1 ratio), 7.28 (d, J=2.51 Hz, 1H), 7.53 (dd, J=8.78, 2.01 Hz, 1H), 7.80-7.90 (m, 3H)
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN(/[CH:7]=[C:8]1\[C:9](=O)[CH2:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]\1)C>C(O)C>[CH3:1][N:2]1[C:9]2[CH2:10][N:11]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][C:8]=2[CH:7]=[N:3]1
Reactant: CNN
Reactant: CN(C)/C=C1/CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Solvent: CCO
Product: Cn1ncc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
A solution of methyl hydrazine (0.11 mL) and (4Z)-4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one (678 mg) in ethanol (5 mL) was heated at 84° C. in a sealed tube for 3 h. Solvent was removed under reduced pressure and the residue was purified on a Biotage Horizon® system (silica, 5% methanol/0.5% concentrated ammonium hydroxide/94.5% dichloromethane) to yield 1-methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:25]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:41]=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:41][C:40]1[CH:43]=[CH:44][C:45]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:38]([O:37][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:39]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C=C(Br)Br)cc1OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a well stirred solution of CBr4 (6.99 g, 21.1 mmol) in dry CH2Cl2 at 0° C. was added PPh3 (11.05 g, 42.1 mmol) and 3,4-bis-dodecyloxy-benzaldehyde (10.0 g, 21.1 mmol). The resulting mixture was stirred for 1 h at ambient temperature. The reaction mixture was solidified during the time. The solid was dissolved in CH2Cl2, washed with H2O, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give an off-white solid. The product was further purified by column chromatography (silica gel, hexanes:dichloromethane=2:1 (v/v)) to give a yellowish white solid (11.37 g, 85.6%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:13][CH3:14])[C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1)#[N:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([O:13][CH3:14])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ncc(C#N)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C#N)cnc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 1-L flask, the methyl 5-cyano-3-methoxypicolinate (step 2, 4.51 g, 23.5 mmol) was taken up in THF (74 mL). The suspension was cooled to 0° C., and sodium hydroxide (1M, 24.64 mL, 24.64 mmol) was added. After 1 h, the reaction was concentrated under reduced pressure. The residue was taken up in 100 mL of water, and the aqueous phase was extracted with diethyl ether (50 mL), which was discarded. The aqueous phase was acidified with HCl (5M, 5.16 mL, 25.8 mmol). The aqueous phase was extracted with DCM (11×150 mL). The combined organic extracts were dried over MgSO4 and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid. MS m/z=179 [M+H]+. Calculated for C8H6N2O3: 178. 1H NMR in CDCl3 δ: 8.48 (d, 1H, J=1.6), 7.71 (d, 1H, J=1.6), 4.08 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH3:21])=[CH:16][CH:15]=1
Reactant: CNc1ccc(F)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(N(C)c2ccc(F)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol) and (4-fluoro-phenyl)-methyl-amine (125 mg, 2.52 mmol) by a procedure similar to example 28 (46.8%). 1H NMR (CDCl3): 7.76 (dd, J=0.9 Hz, J=8.3 Hz, 1H), 7.58-7.52 (m, 1H), 7.16-7.00 (m, 6H), 3.60 (s, 3H), 2.73 (s, 3H),
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:27][OH:28].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:28][NH:27][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12m) (125 mg, 0.320 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (225 mg, 3.20 mmol) and a freshly prepared solution of sodium methoxide in methanol (110 mg, 4.80 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h (progress of the reaction was monitored by TLC analysis). The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethylacetate (5 mL) and the combined organic layers were dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13m. HPLC: (Rt=3.89 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]([C:12]#[N:13])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:4]=1>[Ni].N.CO>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][NH2:13])[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:4]=1
Reactant: COc1nn(C2CCCCO2)c2cccc(C#N)c12
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1nn(C2CCCCO2)c2cccc(CN)c12
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A mixture of 3-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (140 mg, 0.544 mmol) and Raney nickel (20 mg) in NH3/MeOH (7N, 10 mL) was stirred under hydrogen overnight. The reaction mixture was filtered with Celite® and the filtrate concentrated in vacuo to afford (3-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanamine as an oil (119) 130 mg, 91.4%). MS (ESI): m/z=262 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[S:37]1[CH:41]=[CH:40][C:39](C2C=C(B(O)O)C=CC=2)=[CH:38]1>>[C@@H:24]1([N:6]([CH2:5][C:4]2[CH:34]=[CH:35][CH:36]=[C:2]([C:39]3[CH:40]=[CH:41][S:37][CH:38]=3)[CH:3]=2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: OB(O)c1cccc(-c2ccsc2)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccsc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-(3-thienyl)phenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([Si](C)(C)C)#[C:20][CH2:21][CH3:22].I[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37](=[O:39])[CH3:38])[CH:32]=[CH:31]2>C(OCC)(=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:19]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37](=[O:39])[CH3:38])[CH:32]=[CH:31]2)#[C:20][CH2:21][CH3:22]
Reactant: CC(=O)n1ccc2cc(I)ccc21
Reactant: CCC#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CCC#Cc1ccc2c(ccn2C(C)=O)c1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
To a degassed (3× vacuum/nitrogen cycles) solution of TBAF (3.56 mL, 0.5 M THF, 1.78 mmol), but-1-yn-1-yltrimethylsilane (250 mg, 1.98 mmol; Intermediate 39) was added. The solution was stirred at rt for a few minutes before transferring into a reaction vessel containing 1-(5-iodo-1H-indol-1-yl)ethanone (254 mg, 089 mmol), Pd(PPh3)4 (203 mg, 0.18 mmol), and CuI (69 mg, 0.36 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), washed (50 mL saturated NaHCO3 then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as orange oil (180 mg, 96%). 1H NMR (300 MHz, DMSO-d6): δ 8.26 (d, 1H), 7.89 (d, 1H), 7.64 (d, 1H), 7.32 (dd, 1H), 6.71 (d, 1H), 2.64 (s, 3H), 2.40 (q, 2H), 1.18 (t, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:64]1([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1>O.CN(C=O)C.ClCCl>[N:64]1([CH:69]2[CH2:74][CH2:73][N:72]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:18]4[N:17]=[C:16]5[N:12]([CH2:11][C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[N:13]=[N:14][C:15]5=[CH:20][CH:19]=4)=[CH:22][CH:23]=3)=[O:27])[CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
To a solution of example 8 (0.100 g, 0.262 mmol) in 1:1 DMF/dichlormethane mixture (1.0 ml), BOP (0.121 g, 0.275 mmol) and triethylamine (0.1 ml, 0.786 mmol) were added and stirred for 30 min, 4-(pyrrolidin-1-yl)piperidine (0.044 g, 0.288 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.017 g. 12%), M.P.: 132-135° C., 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.33 (d, J=8.2 Hz, 2H), 8.19 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 8.00 (s, 1H). 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H), 3.49-3.10 (m, 9H), 2.07-1.53 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Br:19])[CH:12]=[C:11]([C:20]([O:22]CC)=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O[Li].O.Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Br:19])[CH:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2c(Br)cccc2c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
Ester 8 (2.29 g, 5.94 mmol) was dissolved in a 3:1:1 mixture of THF:CH3OH:H2O (0.1 M). LiOH—H2O was added and the reaction mixture was stirred at 25° C. for 24 h. Upon completion, the reaction mixture was acidified to pH 1 with the addition of 10% aqueous HCl. A precipitate formed during the acidification and it was collected by vacuum filtration. The remaining aqueous layer was then extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The filtered and extracted products were combined to give 9 (2.09 g, 100%) as a pale yellow solid. 1H NMR (DMSO-d6, 500 MHz) δ 8.23 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.91 (d, J=6.5 Hz, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.55 (s, 1H), 7.43-7.39 (m, 3H), 7.33 (t, J=7.0 Hz, 1H), 5.35 (s, 2H). 13C NMR (DMSO-d6, 125 MHz) δ 166.7, 153.8, 136.2, 135.9, 135.0, 129.8, 128.8, 128.2, 127.8, 127.7, 127.5, 124.7, 123.8, 115.5, 107.0, 70.4. IR (film) νmax 3368, 2969, 1680 cm−1. ESI-TOF HRMS m/z 357.0125 (M+H+, C18H13BrO3 requires 357.0121).
Reaction SMILES: [CH3:1][C:2]([CH:9]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]2[C:16]2[CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:12][C:11]=2[NH:10]1)([CH3:8])[CH2:3][S:4]C(=O)C>CO.O1CCCC1.[OH-].[Na+]>[CH3:8][C:2]([CH:9]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]2[C:16]2[CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:12][C:11]=2[NH:10]1)([CH3:1])[CH2:3][SH:4]
Reactant: CC(=O)SCC(C)(C)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CS)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Temperature: 50 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
The compound of Example 76 (134 mg) was dissolved in 15 ml of a mixed solution of methanol and tetrahydrofuran, and 15 ml of a 2 mol/l sodium hydroxide solution was added. After overnight stirring at 50° C., the reaction mixture was concentrated under reduced pressure. The resulting residue was acidified with saturated ammonium chloride solution and 2 mol/l hydrochloric acid solution, and then ethyl acetate was added. The ethyl acetate layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvents: hexane:ethyl acetate 4:1˜hexane:ethyl acetate=2:1˜hexane:ethyl acetate=1:1) to obtain 34 mg of the captioned compound. Its physical properties are shown below.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH3:32])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 23.1 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and ethyl iodide (153 mg, 0.984 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 23%).