Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:37])([F:36])[C:17]([N:19]([C@@H:27]1[CH2:29][C@H:28]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:18].[CH:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][CH:41]=1)=O.[Cl:51]CCCl>>[ClH:51].[F:37][C:16]([F:15])([F:36])[C:17]([N:19]([CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:38][C:40]2[CH:41]=[CH:42][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:44][CH:45]=2)[CH2:25][CH2:26]1)[C@@H:27]1[CH2:29][C@H:28]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18]
Reactant: ClCCCl
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CS(=O)(=O)Nc1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Added sodium triacetoxyborohydride (180 mg, 0.850 mmol) to a solution of 2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (185 mg, 0.567 mmol), N-(4-formylphenyl)methanesulfonamide (124 mg, 0.624 mmol) in 1,2-Dichloroethane (DCE) (40 mL). Let stir at RT for 16 hours. Added 100 mg of sodium triacetoxyborohydride and let stir at RT for 16 hours. Concentrated on a rotovap. Added water and extracted with DCM. Combined DCM extracts and washed with brine, dried over MgSO4, filtered and rotovapped off DCM. The residue was purified via Biotage (0% to 100% EtOAc:Hex then 0% to 20% MeOH:DCM 25 g-HP—silica gel column). Obtained 210 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (br. s., H), 1.90 (br. s., 4H), 2.08-2.27 (m, 3H), 2.39 (br. s., 1H), 2.65 (s, 1H), 3.04 (br. s., 4H), 3.23-3.76 (m, 3H), 4.14 (br. s., 2H), 6.99-7.15 (m, 2H), 7.2-7.3 (m 3H), 7.46 (br. s., 23H), 7.63 (br. s., 2H), 9.05 (br. s., 1H), 11.69 (br. s., 1H)
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Zr+4:5].[Li+:6].[Li+:7].[Li+:8].[NH2-:9]>>[N:9]([Li:8])([Li:7])[Li:6].[Cl-:1].[Cl-:1].[Cl-:1].[Cl-:1].[Zr+4:5]
Reactant: [Li+]
Reactant: [NH2-]
Agent: [Zr+4]
Agent: [Cl-]
Product: [Li]N([Li])[Li]

Procedure:
A mortar and pestle was used to mix 4.434 gram of zirconium tetrachloride (ZrCl4) and 0.882 gram of lithium nitride (Li3N) in order to form the reactant mixture with a stoichiometric ratio of Li3N to ZrCl4 of 4/3. The reactant mixture was placed in a 45 milliliter stainless steel container. A screw top cap was placed on the stainless steel container. The screw top cap had two insulated leads protruding therethrough, which held a nichrome filament in the reactant mixture. An external electric charge was applied to the leads for no more than two seconds thereby igniting the reactant mixture. The resulting yellow-brown product was washed with methanol, dried and then ground with a mortar and pestle. The product was further washed with ten percent nitric acid, methanol, water and acetone on a vacuum filter. The powder was then dried on a vacuum line. The resulting light-brown product was pure ZrN with a cubic lattice spacing of 4.57 Angstroms as determined by X-ray powder diffraction. Use of the Scherrer equation gave a calculated particle size of 500-600 Angstroms. The product yield was ninety-one percent (1.822 grams out of 1.998 grams theoretically possible). A pressed disc indicated metallic type conductivity. A balanced equation is as follows:
Reaction SMILES: C(N(CC)CC)C.[P:8]([O-:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[F:16][C:17]([F:34])([F:33])[C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([OH:28])[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=1>C(Cl)(Cl)(Cl)Cl>[CH2:10]([O:9][P:8]([O:12][CH2:13][CH3:14])([O:28][C:22]1[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=[C:18]([C:17]([F:33])([F:16])[F:34])[C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:15])[CH3:11]
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)Oc1cc(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Triethylamine (25.2 ml, 0.18 mol) was added dropwise to a cooled (0° C.) solution of diethyl phosphite (23.2 ml, 0.18 mol) and product of Example 4 (50.0 g, 0.17 mol) in carbon tetrachloride (100 ml). The reaction mixture, which had developed a heavy flocculent precipitate, was stirred at 0° C. for 30 minutes before being warmed to room temperature for an additional 24 hours. The reaction mixture was washed consecutively with 1N aq hydrochloric acid (1×250 ml), 0.5N aqueous sodium hydroxide (4×100 ml) and water (1×250 ml) before being dried (MgSO4), filtered and evaporated (aspirator) to a yellow oil (61.53 g). Kugelrohr distillation (120° C. at 25 Pa) afforded the product as a very pale yellow oil (59.03 g). Yield-82%, nD25 1.4197.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([OH:24])=O)[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1.CN(C1C=CC=CN=1)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH2:49]([O:51][C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)[CH3:50].C(O[C@H]1CCNC1)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([N:54]4[CH2:55][CH2:56][C@H:52]([O:51][CH2:49][CH3:50])[CH2:53]4)=[O:24])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1
Reactant: CCO[C@H]1CCNC1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCO[C@H]1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2cc(Cl)ccc2CC3)C1
Reaction time: 3 h
Yield: 85 %

Procedure:
A suspension of 8.79 g (25 mmol) of 10-chloro-4-oxo-3-phenyl-6,7-dihydro-4H-benzo[a]quinolizine-1-carboxylic acid (X) in 125 ml of ethyl acetate was treated with 0.076 g (0.625 mmol) of dimethylaminopyridine and 3.49 g (27.5 mmol) of oxalyl chloride. The mixture was then stirred at 600 for 3 hours. The yellow solution (XI) was concentrated and the residue was taken up in 125 ml of toluene. This was treated either with 5.26 g (52 mmol) of triethylamine and 3.94 g (26 mmol) of (S)-3-ethoxypyrrolidine hydrochloride or with 2.63 g (26 mmol) of triethylamine and 3.0 g (26 mmol) of (S)-3-ethoxypyrrolidine and stirred for 4 hours. Subsequently, the solution was washed in succession with 100 ml of water, 100 ml of 1N HCl, 100 ml of 0.5N KHCO3 and then again with 100 ml of water. The individual aqueous phases were extracted with 100 ml of toluene and the combined organic extracts were dried with 20 g of Na2SO4. The residue obtained after filtration and concentration was dried at 50°/0.1 mbar/2 h. Compound I was obtained in 85% yield, based on the acid, after purification by recrystallization from acetone/water and acetone/hexane. M.p. 133°-134°.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:41]=[CH:40][C:21]([O:22][C:23]4[C:28]([C:29]5[CH:34]=[CH:33][N:32]=[C:31]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])[N:30]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(N(C)C)=[O:44].C(N(CC)[P:51]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])C.N1C=NN=N1.OO.O>>[P:51]([O:39][CH2:38][CH2:37][CH2:36][NH:35][C:31]1[N:30]=[C:29]([C:28]2[C:23]([O:22][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:10]4[C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8][N:9]=4)=[CH:41][CH:40]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:34]=[CH:33][N:32]=1)([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:44]
Reactant: CC(=O)N(C)C
Reactant: OCCCNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: OO
Agent: c1nnn[nH]1
Solvent: O
Product: CC(C)(C)OP(=O)(OCCCNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 15 mL RBF under nitrogen was charged with 3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propan-1-ol (130 mg, 0.24 mmol) in DMA (1.2 mL, 0.24 mmol). To this was added di-tert-butyl diethylphosphoramidite (0.14 mL, 0.57 mmol) and 1-H-tetrazole (1.1 mL, 0.49 mmol). The reaction mixture was stirred at RT for 2 hrs, then cooled to −5° C. and hydrogen peroxide −30 wt. % in water (0.05 mL, 0.51 mmol) added slowly via syringe. The reaction was warmed up to RT and stirred for 2 hrs. The reaction was cooled back to −5° C. and quenched with saturated aqueous solution of sodium thiosulfate. The product was extracted into EtOAc, and the organic layer was collected, dried over sodium sulfate and concentrated to afford a crude yellow residue. The residue was purified by ISCO silica gel chromatography (2-5% MeOH/DCM), and the purified fractions were further purified by Gilson RPLC in system (15%-85% CH3CN/H2O/0.1% TFA) to afford di-tert-butyl 3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propyl phosphate. MS m/z=734 [M+H]+. Calc'd for C40H44N7O5P: 733.8.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[OH-].[K+].I[CH3:12]>O1CCOCC1.O>[CH3:1][C:2]1([CH3:12])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1C(=O)CCC1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of 2-methylcyclopentane-1,3-dione (49.98 g, 446 mmol), potassium hydroxide (25.5 g, 455 mmol) and iodomethane (30.1 mL, 481 mmol) in dioxane (390 mL) and water (130 mL) was heated to reflux for 5 h. A biphasic mixture of potassium hydroxide (10.4 g), iodomethane (12.5 mL), water (26 mL) and dioxane (78 mL) was added. The mixture was heated at reflux for 3 additional hours and then stirred at ambient temperature overnight. Another portion of a biphasic mixture of potassium hydroxide (10.4 g), iodomethane (12.5 mL), water (26 mL) and dioxane (78 mL) was added. The mixture was heated at reflux for 3 h, cooled to room temperature and extracted with ether (600 mL, then 2×400 mL). The combined extracts were concentrated using a rotavap while keeping the bath temperature at or below room temperature to prevent loss of volatile product. The residue was treated with 10% hydrochloric acid (250 mL) and placed in a 120° C. oil bath until it started to boil (˜15 min). The mixture was cooled with an ice-water bath, diluted with water (250 mL) and treated with careful addition of sodium carbonate until carbon dioxide release stopped. The pH of the solution was 8-9. The mixture was extracted with dichloromethane (4×200 mL). The combined extracts were dried (MgSO4), filtered and concentrated while keeping water bath at or below room temperature. The residue was further dried under vacuum briefly to remove residual solvent to give 2,2-dimethylcyclopentane-1,3-dione as tan solid (38.1 g, 68% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 2.81 (4H, s), 1.16 (6H, s); LC retention time: 0.990 min (analytical HPLC Method F).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=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:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cccnc1Cl
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: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a de-gassed mixture of 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mmol), p-tolylboronic acid (70.6 mmol), and 2M Na2CO3 (175.0 mmol), in DME (200 mL) under nitrogen add Pd(PPh3)4 (2.8 mmol). Stir the mixture at 80° C. for overnight, concentrate, extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, pass a silica gel pad to give 2-p-tolyl-3-trifluoromethyl-pyridine.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:46][C:47](=[CH2:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:22][CH2:23]1)[OH:20])[CH2:32][C:33]1[N:34]=[CH:35][N:36]([CH2:53][C:47](=[CH2:46])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:37]=1)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(CBr)C(=O)OCC
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(Cn1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 100 mg (0.16 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 46 mg (0.24 mmol) of ethyl 2-(bromomethyl)acrylate and 0.044 ml (0.32 mmol) of triethylamine in 3 ml of methylene chloride is stirred at room temperature under argon for 24 hours. Subsequently, the reaction mixture is evaporated and, for purification, the residue is chromatographed on 30 g of silica gel using a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained mg of ethyl 4-[(S)-2-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-2-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]ethyl]-α-methyleneimidazole-1-propionate as an amorphous solid; MS: 743 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2cscn2)cc1
Yield: 68.7 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.318 g, 0.78 mmol, Example 35, step 3) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithium chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3.5 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.221 g, 68.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.5 %

Procedure:
To a solution of 3,4-dichlorocinnamic acid (21.7 g) and cesium carbonate (22.8 g) in DMF (200 mL) was added methyl iodide (7.47 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, 1M KHSO4 solution and brine and dried, and the solvent was evaporated under reduced pressure to give methyl 3,4-dichlorocinnamate (22.4 g, 97%) as a white powder.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[C:30]([F:31])=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Cl:21][C:22]1[C:30]([F:31])=[C:29]2[C:25]([C:26]([S:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][N:28]2[C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)=[CH:24][CH:23]=1
Reactant: CCCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Reactant: CCOC(=O)c1cccc(S)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 0.83 h
Yield: 60.7 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (66 mg, 0.36 mmol) in CH2Cl2 (5 mL) under inert atmosphere was added NCS (48.2 mg, 0.36 mmol) at RT and stirred for 50 min. To this, compound 3 (100 mg, 0.36 mmol) was added at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 9% EtOAc/Hexanes to afford compound 4 (100 mg, 61%) as a colorless syrup. 1H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H), 7.77-7.76 (m, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 7.27-7.24 (m, 3H), 7.15-7.12 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.15 (t, J=7.0 Hz, 2H), 1.98-1.94 (m, 2H), 1.35 (t, J=7.5 Hz, 3H), 0.98 (t, J=7.0 Hz, 3H); LC-MS: 94.6%; m/z 458.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.91 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][CH:25]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:29][C:27]2[S:28][C:24]([CH3:23])=[C:25]([CH3:30])[N:26]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: Cc1cnc(N)s1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)sc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
800 mg (2.40 mmol) of trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Example 1 Step 3) and 274 mg (2.40 mmol) of 5-methylthiazol-2-amine are placed in a flask with 40 mL of DCM. 191 mg (3.60 mmol) of sodium triacetoxyborohydride is added and the RM is stirred at room temperature overnight 1N sodium hydroxide (2 mL) is added and the mixture is stirred at RT for 10 min. The RM is partitioned between DCM and water. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo. The product is purified by ISCO Combiflash Rf (80 g Si, iso-hexane->EtOAc, default setting). The product crystallised out on the column and had to be eluted with EtOAc (10% MeOH). The solvent is removed in vacuo and the product is crystallised from EtOAc, filtered and dried for 4 days under vacuum @ 50° C.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:6]>>[OH2:2].[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH:4]=[O:2])=[O:6])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[Se]=O
Product: O
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
In the same manner as above, selenium dioxide is reacted with 4-hydroxyacetophenone (VII) to obtain 4-hydroxyphenylglyoxal hydrate (VIII), which is reacted with diaminomaleonitrile (VI) to obtain a phenol derivative (IX), which is then reacted with a corresponding carboxylic acid chloride in the presence of pyridine to obtain the objective compound (I).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=[O:15])[NH:13][CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1.[H-].[Na+].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[Br:1][C:2]1[C:3]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=[O:15])[N:13]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CNC4=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CN(CC2CC2)C4=O)CC1

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-7-bromo-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 93), sodium hydride and l-(bromomethyl)cyclopropane, to give the product as a white solid (55%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:12][C:11]=2[O:10]1.[CH2:25]([C:27]1[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[CH3:26].Cl[Sn](Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[CH2:25]([C:27]1[O:31][C:30]([C@@H:32]2[C:14]3[C:13](=[CH:12][C:11]4[O:10][CH2:9][O:17][C:16]=4[CH:15]=3)[CH2:18][CH2:19][C@H:20]2[C:21]([OH:23])=[O:22])=[CH:29][CH:28]=1)[CH3:26]
Reactant: COC(=O)CCCc1ccc2c(c1)OCO2
Reactant: CCc1ccc(C=O)o1
Agent: CC(C)[N-]C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc([C@@H]2c3cc4c(cc3CC[C@H]2C(=O)O)OCO4)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a freshly prepared solution of LDA (15 mmol) in 30 mL of THF cooled to -78° C. was added a solution of 3,4-methylenedioxybenzenebutanoic acid, methyl ester (14 mmol), from step 558 above, in 10 mL of THF. The solution was stirred for 5 minutes, and a solution of 5-ethylfuran-2-carboxaldehyde (13.8 mmol), from step 55b above, in 30 mL of THF was added. The reaction mixture was warmed to 0° C., and the reaction was quenched with 10 mL of satd NH4Cl. The organic layer was separated, and the aqueous layer was extracted with ether. The organic layers were combined, dried and concentrated. The residue was dissolved in 50 mL of methylene chloride, and the solution was cooled to 0° C. To this solution was added a solution of SnCl4 (1M, 13 mmol) in methylene chloride, and the reaction mixtrue was stirred for 5 minutes. The reaction was quenched with 1 N HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried, filtered and concentrated. The crude methyl ester intermediate was hydrolyzed with KOH in methanol by standard procedures, and the title product was isolated (3.04 g). NMR (CDCl3) δ:6.56 (s, 1H), 6.54 (s, 1H), 5.91-5.81 (m, 4H), 4.39 (d, J=7 Hz, 1H), 3.13 (m, 1H), 2.80 (t, J=7 Hz, 2H), 2.59 (q, J=8 Hz, 2H), 2.18-1.96 (m, 2H), 1.20 (t, J=8 Hz, 3H).