Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][N+:14]#[C-:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH:17]([CH:21]1[CH2:23][CH2:22]1)[CH2:18][CH2:19]Br.O>C(OCC)C.CS(C)=O>[CH:21]1([CH:17]2[CH2:18][CH2:19][C:13]2([N+:14]#[C-:15])[S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:23][CH2:22]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: BrCCC(Br)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: [C-]#[N+]C1(S(=O)(=O)c2ccc(C)cc2)CCC1C1CC1
Reaction time: 1.5 h

Procedure:
In a sulfonation flask 11.1 g (0.28 mol) sodium hydride was suspended in a mixture of 80 ml diethylether and 220 ml DMSO. Then a solution of 19.9 g (0.1 mol) TosMIC and 28.2 g (0.115 mol) (1.3-dibromopropyl)cyclopropane in 30 ml diethylether and 80 ml DMSO was added in 90 minutes. After stirring for 1.5 hours, 70 ml of water was added slowly under ice cooling. The first crop of product was filtered off (16.3 g) and the mother liquor evaporated. The raw material obtained from the mother liquor was then purified by flash chromatography over silicagel (eluent: hexane/ethylacetate 2:1). Overall yield: 19.0 g (68% of theory) of 1-(2-cyclopropyl-1-isocyanocyclobutanesulfonyl)-4-methylbenzene in the form of a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[OH:16])([CH3:3])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.C[N:27](C=O)C>>[CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:6]([C:7]([NH2:27])=[O:8])[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)O)c(O)c(C(C)C)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)c1cc(C(N)=O)c(O)c(C(C)C)c1
Yield: 40 %

Procedure:
To a solution of 3,5-diisopropylsalicylic acid (Aldrich) (10 mmole, 2.2 g) and dichloromethane (20 mL), oxalyl-chloride (Merck) (11.0 mmole, 1.03 mL) and DMF (Aldrich) (80 μL) were added. The reaction mixture was refluxed for 1 hour, whereupon the solvent and the excess of oxalyl-chloride were removed under reduced pressure. The obtained oily product was dissolved in dichloromethane (50 mL) and ammonia gas was introduced into reaction mixture under cooling. The solution was diluted with water and, after drying with sodium sulfate, the organic layer was evaporated under reduced pressure. A yellow residue was recrysatallized from n-hexane, whereat there were obtained 876 mg (40%) of 3,5-diisopropyl salicylamide in the form of a white crystalline product:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.Br[C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>C(Cl)Cl>[CH3:19][CH:15]1[CH2:20][C:11]2[C:10](=[CH:9][C:8]3[CH2:7][CH2:6][CH2:5][C:13]=3[CH:12]=2)[C:16]1=[O:17]
Reactant: CC(C)(Br)C(=O)Br
Reactant: c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1=O)CCC3
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.8 %

Procedure:
50.71 g (377 mmol) of anhydrous aluminum trichloride were slowly added at 0° C. to a mixture of 19.3 g (163 mmol) of indane and 38.3 g of 2-bromoisobutyryl bromide in 500 ml of methylene chloride over a period of 30 minutes. The reaction mixture became dark red. The suspension was stirred at room temperature for 17 hours and subsequently poured onto 200 g of ice. The phases were separated. The organic phase was washed once with 200 ml of 1 normal hydrochloric acid, twice with 200 ml each time of saturated sodium hydrogencarbonate solution and twice with 200 ml each time of water. The organic phase was dried over anhydrous sodium sulfate and filtered. Removal of the solvent under reduced pressure gave 30 g (99% yield) of the compound (1a) as reddish brown oil. According to GC-MS, the content of (1a) in the oil was 99%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH:8][O:9][CH3:10])=[C:5]([S:13][CH3:14])[CH:4]=1.[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22](Cl)=[O:23])[C:18](=[O:25])[O:17]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22]([N:8]([CH2:7][C:6]2[CH:11]=[CH:12][C:3]([F:2])=[CH:4][C:5]=2[S:13][CH3:14])[O:9][CH3:10])=[O:23])[C:18](=[O:25])[O:17]1
Reactant: CONCc1ccc(F)cc1SC
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(Cc1ccc(F)cc1SC)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a stirred solution of N-(4-fluoro-2-methylsulfanyl-benzyl)-O-methyl-hydroxylamine hydrochloride (1.19 g, 5 mmol) and (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.953 g, 5 mmol) in CH2Cl2 (20 mL) was added diisopropyethylamine (1.9 mL, 11 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was taken up into ether (150 mL), washed with 1N HCl (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give product as a white solid (1.77 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 7.28–7.23 (1H, m), 6.90 (1H, dd, J=9.5, 2.6 Hz), 6.78 (1H, td, J=8.4, 2.6 Hz), 6.37 (1H, s), 4.88 (2H, s), 3.62 (3H, s), 2.44 (3H, s), 1.71 (6H, s). MS calcd for C16H18FNO5S Na (M+Na): 378.078; found: 378.18.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])/[CH:27]=[CH:28]/[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CSC>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])[CH2:27][C@H:28]([C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)c1cccc([C@@H](CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccccn2)c1
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a 1.0 M solution of isopropylmagnesium chloride (1.0 mL, 2.08 mmol) in THF was added 2-bromopyridine (0.198 mL, 2.08 mmol) and the mixture was stirred for 1.5 hours. This dark solution, at 0° C., was quickly added to a cooled (−40° C.) solution of CuBr.DMS complex (0.206 g, 1.01 mmol) in THF (2 mL) and dimethylsulfide (1 mL), and the resulting mixture was stirred at −40° C. for 10 min, then placed in an ice bath. Tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate from the previous step, dissolved in THF (2 mL), was added dropwise and the mixture was stirred for 1.5 hours. The reaction was quenched with 20% aqueous NH4Cl solution, the dimethylsulfide was removed under reduced pressure and the mixture was partitioned between EtOAc and H2O. The layers were separated, the water layer was extracted with EtOAc, and the combined organics were washed with H2O and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 10 g ISCO column using 0-40% EtOAc/hexanes over 40 min. The lower diastereomer was combined to give tert-butyl 3-{(1R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxo-1-pyridin-2-ylpropyl}benzoate as an oil (0.12 g, 37%). Absolute chirality was assigned based on literature precedent. TLC Rf=0.3 (1:1 EtOAc:hexanes, UV visualization); HPLC RT=2.1 min, method B; M+H=488.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([NH:10][C:11]1[CH:23]=[CH:22][C:14]2[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][O:21][C:13]=2[CH:12]=1)(=[O:9])=[O:8].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:6][S:7]([NH:10][C:11]1[CH:23]=[CH:22][C:14]2[O:15][CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=3)[CH2:19][CH2:20][O:21][C:13]=2[CH:12]=1)(=[O:8])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc1

Procedure:
To tetrahydrofuran add 9-[(methylsulfonyl)amino]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, pyridine, and 4-[(methylsulfonyl)amino]benzoyl chloride. Monitor the progress of the reaction by thin-layer chromatography. Upon completion, remove the solvent in vacuo. Partition the residue between aqueous NaHCO3 and EtOAc. Separate the layers and wash the organic layer with 1M aqueous HCl. Separate and dry (Na2SO4) the organic layer. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]=[S:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:12]=[S:13]1[CH2:18][CH2:17][CH2:16][CH:15]([O:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14]1
Reactant: O=S1CCCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCCS(=O)C2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (3.65 g, 0.019 mole) was added to a solution of 1-oxo-3-thianol (2.14 g, 0.016 mole) and 4-dimethylaminopyridine (3.9 g, 0.032 mole) in 80 ml. methylene chloride cooled to 0° C. under nitrogen. After 30 min. at 0° C. the reaction was stirred at room temperature overnight. The solution was then washed with 50 ml. 1N aqueous hydrochloric acid solution, 50 ml. water and 50 ml. brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (1 kg), eluting with acetone 1 hexane (4:1) to yield 300 mg. of the trans title compound, 1.4 g. of a mixture of cis and trans title compound and 1.5 g of cis title compound (70% total yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:11]Br.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([Br:11])=[CH:6][N:7]=1
Reactant: BrBr
Reactant: NC(=O)c1nccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1nc(Br)cnc1N
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution 3-aminopyrazine-2-carboxamide (3 g, 22 mmol) in acetic acid (25 mL) was drop wise added bromine (4.2 g, 26.5 mmol) at room temperature the reaction mixture was stirred for 0.5 h and Na2CO3 (2 eq) was added slowly. Upon added of the reaction, the solvent was removed in vacuo, water (50 mL) was added to the residue and the precipitate was collected on a filter and washed with hexane (50 mL) to give 3-amino-6-bromopyrazine-2-carboxamide (4.5 g) as a yellow solid: MS (EI) for C5H5BrN4O: 217 (MH+).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[C:24]([CH:29]=[CH2:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Li])CCC.Cl>C1COCC1.O>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([B:1]([OH:6])[OH:2])=[C:24]([CH:29]=[CH2:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=Cc1cc(OCc2ccccc2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(OCc2ccccc2)ccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 602.9 %

Procedure:
Triisopropyl borate (683 mg, 3.63 mmol) was added to a stirred solution of 4-(benzyloxy)-1-bromo-2-vinylbenzene (1.0 g, 0.346 mmol) in THF (9 mL). The solution was cooled in a CO2/acetone bath. A solution of n-butyllithium (1.45 mL of 2.5M in hexanes, 3.63 mmol) was added dropwise over 5 minutes. The cooling bath was left in place and was allowed to warm to room temperature. The mixture was treated with HCl (5 mL of 1N) and water (5 mL), stirred for 1 hour, and extracted with ethyl acetate (3×15 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to an oil which crystallized from diethyl ether/hexanes to provide colorless crystals of the desired product (530 mg, 57% yield). 1H NMR (300 MHz, CDCl3) δ 5.14 (s, 2H), 5.34 (d, J=12.44 Hz, 1H), 5.68 (d, J=17.57 Hz, 1H), 6.97 (dd, J=8.42, 2.56 Hz, 1H), 7.36 (m, 6H), 7.83 (dd, J=17.57, 10.98 Hz, 1H), 8.16 (d, J=8.42 Hz, 1H).
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])[C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:12][C:4]1[NH:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:2]2[C:3]=1[C:13](=[O:15])[N:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:25]=2
Reactant: CCOC(=O)c1c(C)nc2ccccc2c1Cl
Reactant: NNc1ccccc1
Product: Cc1[nH]c2ccccc2c2nn(-c3ccccc3)c(=O)c1-2

Procedure:
The title compound was synthesized following the procedure described in step 3 using 3g and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 2.77 (3H, s), 7.13 (1H, t, J=7.42 Hz), 7.45 (3H, m), 7.62 (2H, m), 8.20 (3H, m). m/z 276.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)([CH2:21][NH:22][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Reactant: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
To a stirred solution of 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.24 mmol) in CH2Cl2 (1.0 mL) at room temperature under Ar was added isobutyl chloroformate(0.033 mL, 0.26 mmol, 1.1 eq.) followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 h, diluted with EtOAc (5 mL), washed with saturated aqueous NaHCO3 (5 mL) and saturated brine (5 mL) and dried over Na2SO4. Filtration and rotary evaporation gave the crude 4-(4-iodo-phenyl)-4-(isobutoxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.075 g, 0.15 mmol, ˜62%). 1H NMR (300 MHz, CDCl3): δ 7.81 (d, 2H), 7.15 (d, 2H), 4.42 (br.t, 1H), 3.88 (d, 2H), 3.79 (m, 2H), 3.42 (br.m, 2H), 3.25 (br.t, 2H), 2.13 (br.m, 3H), 1.88 (m, 3H), 1.54 (s, 9H), 0.99 (d, 6H). MS: 417 (M−Boc).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cnccc2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccccc1-c1nc2cnccc2s1
Yield: 72.7 %

Procedure:
A suspension of 2-(2-nitrophenyl)thiazolo[4,5-c]pyridine (1.170 g, 4.6 mmol), Fe powder (1.26 g, 22.8 mmol) and NH4Cl (1.97 g, 36.8 mmol) in CH3OH : H2O (4:1, 80 mL) was refluxed for 6 hrs. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was poured into water. The precipitate was collected by filtration, and washed with water (20 mL×3) to afford 2-thiazolo[4,5-c]pyridin-2-yl-phenylamine as a yellow solid (0.760 g, yield: 73%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:13]([NH:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH3:14])[C:10]([OH:12])=[O:11].[C:23](OC=O)(=[O:25])C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:13]([N:15]([CH:23]=[O:25])[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH3:14])[C:10]([OH:12])=[O:11]
Reactant: CC(=O)OC=O
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1cccs1)C(=O)O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1cccs1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of (2R,3S)-2-(3-(thiophene-2-yl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (91 mg, 0.278 mmol) in pyridine (1 mL) at 0° C. is added formic acetic anhydride (0.3 mL). The resulting solution is allowed to warm to 25° C., stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(3-(thiophene-2-yl)-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (90 mg, 91% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:15]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)c1ccc2ncccc2c1
Solvent: CO
Product: NC(=O)c1ccc2ncccc2c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
To a solution of methyl quinoline-6-carboxylate (148 g, 0.79 mol) in methanol (600 ml.), aqueous ammonia (800 ml) was added and then stirred at 45° C. for 12 h. The reaction mixture was concentrated to afford the title compound as a dark red solid (120 g, 88%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](Cl)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccco1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccco1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
43.5 g of N-hydroxyphthalimide were added to a solution of 31.1 g of furfuryl chloride in 80 ml of dimethylformamide, and the mixture was cooled to 0° C. 40.6 ml of triethylamine were then added dropwise to the mixture, after which the reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 24 hours. At the end of this time, the reaction mixture was poured into ice-water. The resulting colorless crystals were collected by filtration, to afford 53.1 g of N-furfuryloxyphthalimide, melting at 145-147° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([I:13])=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].[OH-].[K+].O>O1CCCC1>[I:13][C:10]1[C:11]2[S:12][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[NH:8][N:9]=1
Reactant: COC(=O)c1cc2[nH]nc(I)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2[nH]nc(I)c2s1
Temperature: 60 °C
Yield: 50.1 %

Procedure:
To a solution of 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [4.5 g, 14.60 mmol, Intermediate (26)] in tetrahydrofuran (90 mL) is added potassium hydroxide (2.83 g, 50.44 mmol) and water (20 mL). The resulting reaction mixture is heated at 60° C. oil bath under for 2 hours. The solvent is removed in vacuo and dissolved crude in water (20 mL). The water layer is acidified using 2N hydrochloric acid till pH is 5. White solid precipitated are collected and rinsed with water. The filtrate is extracted three times with ethyl acetate (50 mL). The combined ethyl acetate phases are washed with brine and dried over magnesium sulfate and filtered. Combined solids and stirred in heptane and filtered to obtain 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [2.15 g, 50%, Intermediate (29)] as white solid; 1H NMR [(CD3)2SO)]: δ 13.711 (1H, s), 7.832 (1H, s); LC/MS: 294 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.O.N1C=CC=CC=1CC=O>[Zn].C(O)(=O)C>[Cl:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([C:9]([F:11])([F:10])[F:12])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=CCc1ccccn1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cncc(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 7.1 %

Procedure:
Add zinc dust (1.18 g) to a suspension of 2,3-dichloro-5-trifluoromethyl-pyridine (2.0 g, 9.30 mmol) in 80:20 water and acetic acid (5 mL) and stir at 90° C. for 1 h. Add more zinc dust (1g) and stir at 90° C. for an additional 15 min. Cool the reaction mixture to room temperature, filter, and wash with dichloromethane. Carefully concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexane:dichloromethane, to obtain the title compound as a volatile oil (0.120g, 7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([F:17])[C:5]2=O.[C:19](=[N:25][Si](C)(C)C)=[N:20][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([F:17])/[C:5]/2=[N:25]\[C:19]#[N:20]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1c2cc(Br)ccc2OC2(CCCOC2)C1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/c2cc(Br)ccc2OC2(CCCOC2)C1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (220 mg, 0.65 mmol) in anhydrous DCM was added TiCl4 (1 M in DCM, 1.4 mL) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (264 mg, 1.42 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give crude product, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([Cl:28])=[O:25])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 4'-n-decyl-4-carboxybiphenyl (3.10 g) was heated under reflux for 6 hours together with an excessive amount of thionyl chloride, unaltered thionyl chloride was removed by distillation to give about 3 g of 4'-n-decylbiphenyl-4-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 70 °C
Reaction time: 15 h
Yield: 17 %

Procedure:
A round bottomed flask was charged with methyl 6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate (80 mg, 0.21 mmol), methanol (1.8 mL), and sodium hydroxide solution (1.0M, 0.60 mL, 0.60 mmol) then heated to 70° C. with stirring for 15 h. The reaction was then cooled to room temperature and quenched with 1.0M Hydrochloric acid and diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC was then used to provide the title compound (13 mg, 16% yield). MS (ES−) 362.0 (M−H)−. Retention time: 1.93 min Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.