Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:18])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[F:26][C:27]([F:31])=[C:28]([F:30])[F:29].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:18][C:28]([F:30])([F:29])[CH:27]([F:31])[F:26])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: FC(F)=C(F)F
Reactant: Fc1ccc(-c2nc(S)[nH]c2-c2cccs2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Fc1ccc(-c2nc(SC(F)(F)C(F)F)[nH]c2-c2cccs2)cc1

Procedure:
A solution of 14.0 g of 4-(4-fluorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol in 40 ml of dimethylformamide and 1.5 g of diisopropylamine was pressured in a bomb with 4 g of tetrafluoroethylene. The pressure dropped from 160 psi to 0 in 1.5 hrs. The solution was poured into water, stirred until most of gum solidified, filtered and washed with water. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate, concentrated and diluted with 1-chlorobutane. The crystalline product was collected; yield 2.5 g, m.p. 164°-168° C. The residue from the filtrate was chromatographed on silica gel (Silicar CC-4) using chloroform to give 4.1 g, m.p. 167.5°-170° C. The combined 6.5 g was crystallized from 1-chlorobutane to give 5.6 g, m.p. 167°-168.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4](OS(C)(=O)=O)[CH2:3]1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[N+:14]=[N-:15]
Reactant: CN1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCC(N=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
To a stirred solution of methanesulfonic acid 1-methyl-piperidin-3-yl ester (A) (3 g, 0.17 mmol) in DMF (35 cm3) was added sodium azide (11 g, 0.17 mol). The reaction was then heated to 80° C. for 16 h, and allowed to cool before water (80 cm3) was added and the organic material was extracted into ethyl acetate (80 cm3). The aqueous layer was then extracted with a further portion ethyl acetate (60 cm3) and the combined organic collections and washed with saturated aqueous sodium chloride solution (100 cm3). The organic mixture was and dried over sodium sulfate and then evaporated under reduced pressure to afford the title compound as a crude oil, which was used as crude in next reaction.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(Cl)Cl.[Cl:10]Cl.ClCC(=O)[CH2:15][C:16](Cl)=[O:17]>[Cl-].[Na+].O.C(O)C>[CH2:16]([O:17][C:4](=[O:5])[CH2:3][C:2]([CH2:6][Cl:10])=[O:1])[CH3:15]
Reactant: ClCl
Reactant: O=C(Cl)CC(=O)CCl
Reactant: C=C1CC(=O)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCl
Temperature: -15 °C

Procedure:
A reaction tube, having a 1 m length and a hydraulic-inside diameter of 2 mm, was mounted horizontally. While the tube was cooled from the outside with brine of -20° C., the two reactants (in solution form) were fed to the reaction tube in a continuous cocurrent manner. The requisite turbulent flow was achieved and maintained in the reaction tube. The diketene solution consisted of 8.4 kg of diketene (100 moles) and 150 liters of methylene chloride; and the chlorine solution consisted of 7.6 kg of chlorine (107 moles) and 150 liters of methylene chloride. The two solutions were dosed into the tube such that a flow velocity of 1 m/s developed in the tube. The throughput was 162 1 of solution/hr. (Throughput resp. reaction volume: 3,600 1 of solution/1·hr.) The highest temperature measured in the reaction medium was 21° C. Upon emergence from the reactor, the reaction solution had a temperature of 2° C. The solution emerging to the reactor was taken and cooled to -15° C. The γ-chloroacetoacetic acid chloride product was reacted with an equimolar quantity of ethyl alcohol to form γ-chloroacetoacetic acid ethyl ester. Following such, the excess chlorine, as well as the methylene chloride, was removed by distilling it off. Gas chromatographic analysis of the crude γ-chloroacetoacetic acid ethyl ester showed a content of 98.1 percent thereof (plus 0.4 percent of acetoacetic acid ester, zero percent of α-chloroacetoacetic acid ester and 0.3 percent of α, γ-dichloroacetoacetic acid ester).
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[NH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH:11]=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:15]([NH:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH:13]=1)=[O:24]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: CC(C)N=C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of 2-isocyanatopropane (0.050 g, 0.59 mmol), N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (0.047 g, 0.17 mmol) and diisopropylethylamine (50 mg, 0.39 mmol) in 1,2-dichloroethane (3.0 mL) was stirred at 60° C. for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (0.025 g, yield: 41%). 1H NMR (DMSO-d6, 500 MHz): δ 8.02 (d, J=5.5 Hz, 1H). 7.51 (s, 1H), 7.40-7.34 (m, 3H), 7.05 (m, 1H), 3.87 (m, 1H), 1.14 (t, J=6.5 Hz, 6H). LCMS (ESI) m/z: 367.1 [M+H+].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([OH:21])=O)[CH2:17][C:6]=2[CH:5]=1.Cl.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:21])[N:45]3[CH2:44][CH2:43][CH:42]([C:39]4[CH:38]=[C:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:41][N:40]=4)[CH2:47][CH2:46]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(c2cc(-c3ccccc3)[nH]n2)CC1
Yield: 38.2 %

Procedure:
(S)-2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (66 mg, 0.23 mmol) and 4-(5-phenyl-1H-pyrazol-3-yl)piperidine hydrochloride (40 mg, 0.15 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound (34 mg) was obtained as white solid. MS (ESI) 594 (M+H); Rf=1.99.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43]([C:17]2[CH:16]=[CH:15][C:14]([C:12]5[N:13]=[C:8]([C:5]6[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=6)[N:9]=[C:10]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[N:11]=5)=[CH:19][CH:18]=2)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Brc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(-c4ccc5c(-c6ccccc6)c6ccccc6c(-c6ccccc6)c5c4)cc3)n2)cc1
Yield: 79.8 %

Procedure:
2-(4-Bromophenyl)-4,6-diphenyl-1,3,5-triazine 4.3 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.25 g (0.22 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 5.6 g (yield: 80%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that m/e was 637 versus a molecular weight of 637.25 and that it was the aimed compound 6.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:38])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:5]1([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:4][CH2:3]2.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH:42]([C@H:39]1[C@@H:6]2[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@:5]2([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:55])[CH3:56])[CH2:41][CH2:40]1)[C@@:19]1([CH3:20])[C@@H:10]([C@:11]2([CH3:38])[C@@H:16]([CH2:17][CH2:18]1)[C:15]([CH3:21])([CH3:22])[C@@H:14]([C:23]1[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:12]2)[CH2:9][CH2:8]3)([CH3:44])[CH3:43]
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(trimethylsilyl)ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.018 mmol) was dissolved in a mixture of ethyl acetate and methanol (2 ml, 1:1) and treated with palladium (10% in carbon, 1 mg, 9.40 mmol) and a balloon with hydrogen. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and filtered through a fine pad of celite. The solvent was removed in vacuo and the crude was purified in silica gel to afford 2-(trimethylsilyl)ethyl 4-((1S,3aS,5aR,5bR,7aS,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (12 mg, 80%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.28 Hz, 2H), 7.23 (d, J=8.53 Hz, 2H), 6.22 (t, J=6.15 Hz, 1H), 4.50-4.36 (m, 2H), 4.24-4.16 (m, 2H), 3.51 (td, J=11.48, 6.40 Hz, 2H), 2.59-2.49 (m, 2H), 2.40 (dd, J=12.92, 2.89 Hz, 2H), 2.35-2.24 (m, 1H), 2.18-2.04 (m, 1H), 2.03-1.95 (m, 1H), 1.89-0.91 (m, 26H), 0.99 (s, 3H), 0.96 (s, 6H), 0.88 (d, J=7.03 Hz, 3H), 0.77 (d, J=7.03 Hz, 3H), 0.76 (s, 3H), 0.70 (s, 3H), 0.09 (s, 9H), 0.06 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:27])=[CH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NC(C)=O
Yield: 39.7 %

Procedure:
N-[2-(4-Amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (0.72 g, 1.56 mmol) was dissolved in 200 mL of warm ethanol. 10% Palladium on carbon (0.33 g) was added and the mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent, and the filtrate was removed under reduced pressure. The resulting brown solid was purified by flash column chromatography on silica gel, eluting with 14% methanol in dichloromethane. The fractions containing the desired product were combined and further purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used with the eluent being a gradient of 30-50% CMA in chloroform. The clean fractions were combined and concentrated under reduced pressure to provide 0.23 g of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as an off-white solid, m.p. 140° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)O[C:29](=[O:30])C=2C=1.C=O.[OH-].[Na+]>CC(C)=O.O>[OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]=2[CH2:29][OH:30])[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=C(CO)C(=O)CC2)[C@@H]1O
Reaction time: 5 h

Procedure:
2,98 of the title compound of example 5 are dissolved in 150 ml of acetone and a drop of a phenolphtalein-solution and the solution is mixed with 2,5 ml of a 37% formaldehyde solution three times every hour. The pH-value of the solution is kept between 8 and 9 by controlled addition of 0,1 aq. sodium hydroxide-solution. After stirring during 5 hours the reaction solution is diluted with water and the organic components are extracted with dichloromethane. Usual work up yields white crystalls of the title compound having a m.p. of 218°-220° C. (from dichloromethane/ethanol).
Reaction SMILES: [C:1]([C:3]1([OH:13])[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:12])[CH3:11])#[CH:2].Br[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:18]=[CH:19][CH:20]=1>>[F:27][C:26]([F:28])([F:29])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]#[C:1][C:3]2([OH:13])[C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][CH2:7][C:8]2([CH3:9])[CH3:10])[CH:16]=1)=[O:30]
Reactant: C#CC1(O)C(C)(C)CCCC1(C)C
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Product: CC1(C)CCCC(C)(C)C1(O)C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of 1-ethynyl-2,2,6,6-tetramethylcyclohexanol with bromide 10 following the method used in Example 4 gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxy-2,2,6,6-tetramethylcyclohexyl)ethynyl)phenyl)propyl)acetamide as a light brown foam. Yield (0.192 g, 84%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.18-7.23 (m, 3H), 4.92 (s, 1H), 3.18 (q, J=6.8 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.6 Hz, 2H), 1.22-1.50 (m, 6H), 1.14 (s, 6H), 1.04 (s, 6H).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].Cl>CCCCCC.C1COCC1.CCOC(C)=O>[O:24]=[C:23]([CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:22][CH2:21][C:20]([OH:25])=[O:19]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 46.2 %

Procedure:
1.59M n-Butyllithium solution in n-hexane (25 mL) was added dropwise to a stirred solution of 1,1′-methylenedibenzene (6.73 g) in THF (75 mL) below 35° C. under N2 gas atmosphere. The reaction mixture was added dropwise to a solution of dihydrofuran-2,5-dione(2 g) in THF (50 mL) below 25° C. After stirring for 4 hours. 1M HCl aqueous solution (45 mL) and EtOAc were poured into the reaction mixture. The organic layer was separated and was washed with water and brine, and dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH). The desired fractions were collected and evaporated in vacuo to give 4-oxo-5,5-diphenylpentanoic acid (2.48 g) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([CH2:10][NH2:11])[CH2:6][C:7]([OH:9])=[O:8])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH:19]([CH3:39])[C:20]([O:22][CH2:23][CH2:24][O:25][C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)=[O:27])=[O:21].S(=O)(=O)(O)O>C(#N)C.COC(C)(C)C.O>[CH3:3][CH:2]([CH3:1])[CH2:4][C@H:5]([CH2:10][NH:11][C:26]([O:25][CH2:24][CH2:23][O:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:39])=[O:27])[CH2:6][C:7]([OH:9])=[O:8].[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29]([OH:28])=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: CC(C)C[C@H](CN)CC(=O)O
Reactant: CC(C)C(=O)OCCOC(=O)Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@H](CNC(=O)OCCOC(=O)C(C)C)CC(=O)O
Product: CS(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Pregabalin (0.95 g) and water (25 mL) were charged to a vessel at room temperature. Potassium carbonate (0.8 g) was added in one portion and the mixture was stirred at room temperature for 5 minutes. A solution of [4-(methylsulfonyl)phenoxycarbonyloxy]ethyl 2-methylpropanoate D3 (1.6 g) in acetonitrile (25 mL) was added. After 6 hours, tert-butyl methyl ether (50 mL) was added and the reaction mixture was cooled to 5-10° C. A solution of 5% aqueous sulfuric acid was added to adjust the pH to approximately 3. The mixture was then warmed to room temperature and stirred for 10 minutes. The organic layer was washed with water (3×10 mL) and evaporated to yield the title compound E1 as an orange oil with 4-(methylsulfonyl)phenol impurity. The crude product was purified by silica gel chromatography using ethyl acetate and hexane (4:6) to provide 1 g of the title compound E1 as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.N>[Ni].CO.ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 24 h

Procedure:
Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (32 g, 89 mmol) and ethanol (150 mL) in a Parr bottle. Add Raney nickel (100 g) and an aqueous concentrated ammonia solution (40 mL),. Hydrogenate at 50 psi for 24 h. Filter through a celite pad and rinse the solids with ethanol. Evaporate the filtrate invacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 6% methanol/dichloromethane to give the title compound: Rf= 0.34 (silica gel, 6% methanol/dichloromethane); mp; 87°-90° C. Elemental Analysis calculated for C14H15Cl2NO3 : C 53.18; H 4.78; N 4.43; Found: C 53.:34; H 4.71; N 4.51.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][C:21]([O:23]C)=[O:22])[N:11]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)=[CH:27][CH:26]=3)[C:10](=[O:36])[C:7]=2NN=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-:42].[Li+].Cl.[OH2:45]>CO>[OH:23][C:21]([CH2:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:11]([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:35]=[CH:34][S:33][CH:32]=3)=[CH:29][CH:30]=2)[C:10](=[O:36])[C:7]([OH:42])=[C:6]1[C:5](=[O:45])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: [OH-]
Reactant: COC(=O)COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Reactant: O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)C1=C(O)C(=O)N(c2ccc(-c3ccsc3)cc2)C1c1ccccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a mixture of 3-t-butyl-5-(4-thiophene-3-ylphenyl)-4-(2-methoxycarbonylmethyloxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.124 g, 0.25 mmol), THF (1.24 mL) and methanol (1.24 mL) was added 1 mol/L aqueous lithium hydroxide solution (0.74 mL), and the resulting mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, 2 mol/L hydrochloric acid (0.38 mL) and water (10 mL) were poured into the reaction mixture, and the precipitated aimed compound was collected by filtration. The resulting aimed compound was dissolved in ethyl acetate, and the solution was dried over anhydrous sodium sulphate and then concentrated in vacuo. The resulting residue was triturated with ethyl ether and diisopropyl ether to give 5-(2-hydroxycarbonylmethyloxyphenyl)-4-(2,2-dimethylpropionyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.104 g, yield: 87%) as pale brown solid.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:7]=2[C:19]([O:21]C)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:24]>C1COCC1.CO>[CH:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:7]=2[C:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1.[Na+:24]
Reactant: COC(=O)c1cc(-c2cncc(C)c2)cnc1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cncc(-c2cnc(C3CCCC3)c(C(=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-2, 0.060 g, 0.020 mmol, 1.0 equiv) in THF/methanol (1.7 mL/0.3 mL) was added 10 N sodium hydroxide (0.10 mL, 1.0 mmol, 5.0 equiv) and the system was stirred for 18 h at ambient temperature. The reaction mixture was concentrated and azeotroped with ethyl acetate (2×10 mL) and toluene (3×10 mL) to afford the desired product (6-3) as a white solid. ESI+MS [M+H]+ C17H18N2O2 calc'd 283.1, found 283.0.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].Cl.[NH2:17]N.CO.C(Cl)Cl>C(O)CCC>[F:11][C:10]([F:13])([F:12])[C:9]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[NH:2][N:17]=1
Reactant: CN(C)c1ccncc1C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCCCO
Product: FC(F)(F)c1n[nH]c2ccncc12
Temperature: 200 °C
Yield: 84.2 %

Procedure:
A suspension of 1-(4-(dimethylamino)pyridin-3-yl)-2,2,2-trifluoroethanone (259 mg, 1.187 mmol) and hydrazine monohydrochloride (244 mg, 3.56 mmol) in butan-1-ol (2.5 mL) was heated to 200° C. for 35 min. The reaction mixture was applied to a 10 g SPE cartridge that had been pre-conditioned with 3% MeOH/DCM and eluted with the same system to give a light yellow solid (189 mg, 1.0 mmol, 85%).