Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37].O>C(Cl)Cl>[C:36](=[O:37])([O:38][CH3:39])[O:17][C:16](=[O:18])/[CH:15]=[CH:14]/[C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])=[N:11][C:12]=1[CH:19]([CH3:20])[CH3:21]
Reactant: COC(=O)Cl
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)OC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl](2E)-propenoic acid (5 g, 0.012 m) was dissolved in methylene chloride (25 ml) and triethylamine (1.54 g, 0.015 m) was added at 25° C. The mixture was cooled to 0° C. and methyl chloroformate (1.31 g, 0.013 m) was added to the reaction mass slowly over a period of 10 min keeping the temperature below 5° C. The reaction mixture was stirred at 0-5° C. for 30 min and water (25 ml) was added to it. The organic layer was separated and washed with aqueous sodium bicarbonate solution (5% w/v, 20 ml) followed by water (20 ml). Methylene chloride was distilled out under reduced pressure at 40-45° C. to obtain the product as an oily mass, which was crystallized from n-hexane to obtain while crystalline solid (Yield: 5.4 g, 98%).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].Br[C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>C1COCC1.Br[Zn]Br.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: CC(C)[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Br[Zn]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)cc1C(C)C
Temperature: -48 °C
Reaction time: 1 h

Procedure:
To a stiffed mixture of dibromozinc (39.0 g, 173 mmol, 4.00 equiv) in THF (500 mL) under nitrogen at −48° C. was added dropwise isopropylmagnesium bromide (3 M in THF, 170 mmol) over a period of 30 min Pd(dppf)Cl2 (0.5 g, 0.05 equiv) and methyl 2-bromo-4-methylbenzoate (10.0 g, 43.7 mmol, 1.00 equiv) were added to the above reaction mixture. After stirring for 1 h at −48° C., the reaction mixture was quenched by the careful addition of 500 mL of NH4Cl (aq.). The resulting mixture was extracted with 3×500 mL of ethyl acetate. The combined organic layers were washed with 3×500 mL of brine and concentrated in vacuo. The residue was purified using silica gel column chromatography with petroleum ether (1:1) as eluent. This resulted in 6.50 g (77%) of methyl 2-isopropyl-4-methylbenzoate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10]OC)[S:7][C:6]=1[CH3:13].B(Cl)(Cl)[Cl:16]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10][Cl:16])[S:7][C:6]=1[CH3:13]
Reactant: ClB(Cl)Cl
Reactant: COCc1cc(CC(=O)OC)c(C)s1
Solvent: ClCCl
Product: COC(=O)Cc1cc(CCl)sc1C
Temperature: 0 °C
Yield: 99.6 %

Procedure:
A solution of (5-methoxymethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (2.2 g, 10.1 mmol) in dichloromethane (60 mL) is cooled to −65° C. and treated with boron trichloride (10.1 mL, 1.0 M, 10.1 mmol) dropwise via syringe. The mixture is allowed to warm to 0° C., poured into ice-water and extracted with dichloromethane (3×). The combined organic extracts are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give (5-chloromethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (2.2 g, 99%) as an orange oil. 1H NMR (CDCl 3, 300 MHz) δ 6.90 (s, 1 H), 4.72 (s, 2 H), 3.70 (s, 3 H), 3.50 (s, 2 H), 2.38 (s, 3 H).
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C@H:13]([C:24]([NH:26][CH3:27])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.C(N(CC)CC)C.S(=O)(=O)(O)[O-].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:27][NH:26][C:24](=[O:25])[C@H:13]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH:12][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:1]1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: CNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCC[C@@H]1C(=O)O
Reaction time: 2 h
Yield: 48 %

Procedure:
To a mixture of 0.281 g (1.82 mmol) of cis-1,2-cyclohexanedicarboxylic anhydride and 0.47 g of the hydrochloride salt of L-Trp-NHMe in 0.5 mL of dimethylformamide 0.51 mL of triethylamine was added at room temperature. After 2 hr of stirring the resulting mixture was diluted to 10 mL with water and 25 mL of ethyl acetate was added. The resulting mixture was acidified to pH=2 with 10% potassium bisulfate and the organic phase was washed with water (2×15 ml), saturated sodium chloride and dried over anhydrous magnesium sulfate and evaporated to dryness. The title compound 35 was purified by crystallization from an ethyl acetate-hexane mixture. Yield 48%; mp=105°-112° C.; Rf (G)=0.65, 0.61.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([O-:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1.[CH:53]([C:55]1[NH:56][CH:57]=[CH:58][N:59]=1)=[CH2:54].[CH:60]1[CH:65]=[N+:64]([C@@H:66]2[O:70][C@H:69]([CH2:71][O:72][P:73]([O:76][P:77]([O:80][CH2:81][C@H:82]3[O:86][C@@H:85]([N:87]4[C:91]5[N:92]=[CH:93][N:94]=[C:95]([NH2:96])[C:90]=5[N:89]=[CH:88]4)[C@H:84]([OH:97])[C@@H:83]3[OH:98])([OH:79])=[O:78])([O-:75])=[O:74])[C@@H:68]([OH:99])[C@H:67]2[OH:100])[CH:63]=[C:62]([C:101]([NH2:103])=[O:102])[CH:61]=1.[Cl-:104].[CH:105]([N+:107]1[CH:111]=[CH:110][N:109]([CH2:112][C:113]2[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=2)[CH:108]=1)=[CH2:106].[Cl:119][CH2:120][CH2:121][OH:122]>CN(C=O)C>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([O-:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1.[CH:53]([C:55]1[NH:56][CH:57]=[CH:58][N:59]=1)=[CH2:54].[CH:60]1[CH:65]=[N+:64]([C@@H:66]2[O:70][C@H:69]([CH2:71][O:72][P:73]([O:76][P:77]([O:80][CH2:81][C@H:82]3[O:86][C@@H:85]([N:87]4[C:91]5[N:92]=[CH:93][N:94]=[C:95]([NH2:96])[C:90]=5[N:89]=[CH:88]4)[C@H:84]([OH:97])[C@@H:83]3[OH:98])([OH:79])=[O:78])([O-:75])=[O:74])[C@@H:68]([OH:99])[C@H:67]2[OH:100])[CH:63]=[C:62]([C:101]([NH2:103])=[O:102])[CH:61]=1.[Cl-:119].[CH:105]([N+:107]1[CH:111]=[CH:110][N:109]([CH2:112][C:113]2[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=2)[CH:108]=1)=[CH2:106].[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([O-:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1.[Cl-:104].[CH:34]([N+:36]1[CH:40]=[CH:39][N:38]([CH2:120][CH2:121][OH:122])[CH:37]=1)=[CH2:33]
Reactant: OCCCl
Agent: C=C[n+]1ccn(Cc2ccccc2)c1
Agent: C=Cc1ncc[nH]1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Product: C=C[n+]1ccn(CCO)c1
Temperature: 100 °C

Procedure:
A solution of 200 g of a 20.0 wt. % solution of styrene-co-1-vinylimidazole-co-1-vinyl-3-benzylimidazolium chloride (50/40/10) (Compound F-5) in DMF was further quaternized with 3.2 g of 2-chloroethanol by stirring and heating at 100° C. for 18 hr. The reaction mixture was cooled and the polymer precipitated into diethyl ether with rapid stirring. The flaky precipitate was washed well with diethyl ether and dried in a vacuum oven.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCN(C)C)cc2c1=O
Yield: 70.6 %

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.16 g), 2-dimethylaminoethyl chloride hydrochloride (87 mg), potassium carbonate (0.65 g), and sodium iodide (7 mg) were stirred in acetone (8 ml) at 60° C. for 16 hours. The reaction mixture was filtered, the solids washed with acetone, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 2N NaOH solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate+1% aqueous ammonia solution gave N-cyclopropyl-3-[7-[2-(dimethylamino)ethoxy]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (0.137 g) as a white solid; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.23 (s, 6H), 2.68 (t, 2H), 2.85 (m, 1H), 4.19 (m, 2H), 6.72 (d, 1H), 7.21 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.68 (s, 1H), 7.71 (d, 1H), 7.75 (s, 1H), 7.88 (d, 1H), 8.43 (d, 1H): Mass Spectrum: M+H+ 406.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:21])=[C:16]([F:29])[CH:15]=1>C(Cl)Cl>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:21])=[C:16]([F:29])[CH:15]=1
Reactant: COc1ccc(CNc2ccc(S(=O)(=O)Nc3nccs3)c(F)c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reaction time: 1 h
Yield: 55 %

Procedure:
Trifluoroacetic acid (8 mL, 0.1 mol) was added to the mixture of the [A] 4-(2,4-dimethoxy-benzylamino)-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (2.59 g, 0.00612 mol) in methylene chloride (33 mL). The reaction mixture was stirred for one hour (turned into a purple solution) then concentrated to give the crude product, which was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8) to give the product as a yellow solid (0.92 g, 55%).
Reaction SMILES: [Cl:1][C:2]1([C:9]([OH:11])=O)[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1([C:9]([Cl:14])=[O:11])[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)O
Product: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)Cl

Procedure:
The 1,2,2-trichloro-2,2-dimethylcyclopropanecarboxylic acid (3.0 g) synthesized in Example k and thionyl chloride (1.0 ml) were mixed, and reacted at 60° C. The reaction mixture was distilled under reduced pressure to give the desired 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylic acid chloride (2.8 g) represented by the following formula. ##STR26##
Reaction SMILES: I[C:2]1[N:3]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH3:26])[C:18]4[C:23]([C:24]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:27][C:28]1[S:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[CH3:27][C:28]1[S:32][C:31]([C:2]2[N:3]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH3:26])[C:18]5[C:23]([C:24]=4[CH:25]=3)=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:4]=[C:5]([C:7]3[S:8][C:9]([CH3:12])=[CH:10][CH:11]=3)[N:6]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1ccc(-c2cn(-c3ccc4c(c3)c3ccccc3n4C)c(I)n2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cn(-c3ccc4c(c3)c3ccccc3n4C)c(-c3ccc(C)s3)n2)s1
Temperature: 25 °C
Yield: 135.4 %

Procedure:
A mixture of 3-(2-iodo-4-(5-methylthiophen-2-yl)-1H-imidazol-1-yl)-9-methyl-9H-carbazole 10 (920 g, 2.0 mmol), 5-methylthiophene-2-boronic acid pinacol ester (880 mg, 3.9 mmol), Na2CO3 (1.03 g, 9.81 mmol) in H2O (5 mL) and DMF (20 mL) was degassed (N2 bubbling). Pd(PPh3)4 (60 mg) was added and the mixture was heated to reflux for 8 h. The mixture was allowed to cool to room temperature and concentrated. The residue was washed with H2O (3 times) and EtOAc (1 time). The solid material was transferred to a soxlet apparatus and the material extracted with EtOAc. The organic extract was concentrated to ˜10 mL and the solid material was collected and recrystallised (EtOAc) to give 3-(2,4-bis(5-methylthiophen-2-yl)-1H-imidazol-1-yl)-9-methyl-9H-carbazole 11 (1.19 g, 76%) as colourless crystals. A portion of this material was further purified by sublimation (220° C., 10−6 mBar): m.p. 248-255° C. (DSC)1H NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.51 (d, J=0.6 Hz, 3H), 3.94 (s, 3H), 6.48 (br s, 1H), 6.72 (d, J=2.5 Hz, 1H), 7.22 (s, 1H), 7.30 (t, 7.6 Hz, 1H), 7.43 (dd, J 2.0, 8.6 Hz, 1H), 7.49 (d, 8.5 Hz, 2H), 7.57 (dt, J 1.0, 7.6 Hz, 1H), 8.08 (d, 7.7 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.1, 15.4, 109.0, 109.2, 117.9, 119.2, 119.8, 120.8, 122.2, 123.3, 124.5, 125.9, 126.1, 126.9, 141.1, 141.8, 142.6; HRMS (EI) m/z 439.1163 C24H22N2S [M]+. requires 439.1171.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].C(=O)(O)[O-].[Na+].Cl/[C:13](=[N:19]\[OH:20])/[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH:3]1[O:20][N:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: C=CC(F)(F)F
Reactant: CCOC(=O)/C(Cl)=N/O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NOC(C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 60 h
Yield: 84.2 %

Procedure:
To a suspension of 3,3,3-trifluoroprop-1-ene (ca. 4.3 g, 45 mmol) in AcOEt (30 ml) and sodium bicarbonate (6.3 g, 75.0 mmol) was added at −78° C. a solution of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (2.81 g, 18.0 mmol) in AcOEt (6 ml), the suspension was allowed to warm to 22° C. and stirring was continued for 60 h. The suspension was filtered, the filtrate was evaporated and the residue purified by chromatography on silica gel using heptane/AcOEt (10:1) to give ethyl 5-(trifluoromethyl)-4,5-dihydroisoxazole-3-carboxylate (3.2 g) as a colorless oil. MS: m/z=211 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:16](O)[CH3:17]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(O)c1

Procedure:
To a solution of 3-hydroxybenzoic acid (10 g, 72.4 mmol) in Ethanol (150 mL) stirred under nitrogen was added H2SO4 (3.86 mL, 72.4 mmol). The reaction mixture was refluxed at 85° overnight. The reaction mixture was concentrated and partitioned between ethyl acetate 100 mL and water 30 mL. The organic layers were combined and dried over Na2SO4, evaporated in vacuo to give the crude product D45 in 11 g. LCMS Retention time=1.45 mins, [M+H]+167 (5 min run)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1>>[Cl:34][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][NH:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][C:30]=1[OH:33]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: Clc1nccc(-c2cccc(CNCCc3ccncc3)c2)n1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNCCc4ccncc4)c3)n2)cc1Cl

Procedure:
Intermediate 173 from above was coupled with 4-(2-aminoethyl)-2-chlorophenol following procedure F. LC-MS showed the product had the expected M+H+ of 460. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.4 (d, 2H) 8.4 (s, 1H) 8.29 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H) 7.66-7.56 (m, 2H), 7.36 (d, 1H), 7.20 (d, 1H) 7.10 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.3 (s, 2H), 3.6 (t, 2H), 3.3 (t, 2H), 3.0 (t, 2H), 2.8 (t, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:17]1[N:18]=[CH:19][N:20]([CH3:22])[CH:21]=1)[CH2:14][CH2:15]C.CN(C)[CH:25]=[O:26].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:22][N:20]1[CH:21]=[C:17]([CH2:13][CH2:14][CH3:15])[N:18]=[C:19]1[CH:25]=[O:26]
Reactant: CCCCc1cn(C)cn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCc1cn(C)c(C=O)n1
Temperature: -20 °C
Yield: 7.7 %

Procedure:
To a solution of diisopropylamine (0.13 mL, 0.918 mmol) in 2 mL anhydrous tetrahydrofuran at −40° C. was added n-butyllithium (0.34 mL, 2.5 M in hexanes) dropwise. The solution was stirred while warming to −20° C. over 20 minutes. After cooling to −78° C., 4-butyl-1-methyl-1H-imidazole (95 mg, 0.765 mmol) was added dropwise as a solution in 2 mL anhydrous tetrahydrofuran. The resulting solution was stirred for 40 minutes at −78° C. Dimethylformamide (0.24 mL, 3.06 mmol) was added and the solution stirred while warming to room temperature. The reaction mixture was poured into 15 mL of 1 N hydrochloric acid and stirred for 5 minutes. The pH of the reaction mixture was adjusted to 7-8 by careful addition of saturated sodium bicarbonate solution. Organics were extracted with dichloromethane (3×20 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-50% ethyl acetate in hexanes) to give 1-methyl-4-propyl-1H-imidazole-2-carbaldehyde (9 mg, 8%) as an off-white solid. Used without further characterization.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[CH2:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 3-Ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (95 mg, 0.35 mmol), lithium hydroxide monohydrate (120 mg, 2.77 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 67.8 mg (74%). MS m/e 329.9 (M+H+).
Reaction SMILES: [Na].C(S)C.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1>CN(C)C=O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc(CC(CC(=O)O)CC(=O)O)cc1
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(O)CC(CC(=O)O)Cc1ccc(O)cc1
Temperature: 165 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a stirred suspension of 57% sodium hydrideparaffin (1.4 g) in dry dimethylformamide (30 ml) is added dropwise a solution of ethanethiol (4.0 ml) in dry dimethylformamide (10 ml). After 15 minutes, a solution of 3-[(4-methoxyphenyl)methyl]glutaric acid (800 mg) in dry dimethylformamide (20 ml) is added. The resulting slurry is heated in a bath at 165° C. for 20 hours and evaporated in vacuo. The residue is acidified with 20% hydrochloric acid, extracted with ether and the extracts are discarded. The aqueous solution is saturated with salt and extracted with ethyl acetate. The extracts are combined, washed once with brine, dried, evaporated and the residue crystallized from a mixture of ethyl acetate-chloroform-hexane to give 600 mg of 3-[(4-hydroxyphenyl)methyl]glutaric acid, melting point 117°-119° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[C:13]#[N:14])([CH2:3][CH3:4])[CH3:2].N>CO.[Ni]>[CH:1]([C:5]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][NH2:14])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCC(C)c1cc(C)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a suspension of Raney Ni (10 g) in methanol (50 mL) was added 4-sec-butyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (7 g, 36.8 mmol) followed by methanolic ammonia (200 mL) and the resulting reaction mixture was stirred at room temperature under hydrogen pressure (80 psi) for 18 h. The reaction mixture was filtered through Celite pad and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure to afford the crude product (7 g). The reaction was repeated again under same condition. The crude products were combined and purified by silica gel chromatography (eluent: 8% MeOH in CHCl3, spiked with NH3) and the obtained solid was triturated with diethyl ether (50 mL) and dried under vacuum to afford the title compound as yellow solid (3.5 g, 28%). 1H NMR (DMSO-d6, 400 MHz): δ 0.809-0.774 (t, 3H, J=6.8 Hz), 1.113-1.097 (d, 3H, J=6.4 Hz), 1.504-1.468 (t, 2H, J=7.2 Hz), 2.184 (s, 3H), 2.839-2.822 (d, 1H, J=6.8 Hz), 3.822 (s, 2H), 6.059 (s, 1H), 8.315 (bs, 2H); LCMS (ES+) m/z=195.22 (M+H)