Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])=[C:8]([CH3:17])[C:7]=1[CH3:18].S(O)(O)(=O)=O.[NH2:26][OH:27].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:18][C:7]1[C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:3]=[N:26][OH:27]
Reactant: NO
Reactant: CCOCCc1ccc(OCC(OC)OC)c(C)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCCc1ccc(OCC=NO)c(C)c1C
Reaction time: 10 h
Yield: 93 %

Procedure:
A mixture of 2.1 liters of methanolic solution of 760 g of 1-(2,2-dimethoxyethoxy)-4-(2-ethoxyethyl)-2,3-dimethylbenzene and 2.1 liters of aqueous solution of 466 g of hydroxylamine sulfate was heated to 70 C. To the mixture added was 12 N sulfuric acid until the pH became 0.5, and the mixture was stirred vigorously. Since the pH is lowers with the progress of the reaction, an aqueous 12 N sodium hydroxide solution was added dropwise so as to maintain pH at 0.5. The reaction was monitored by HPLC, and when the conversion exceeded 95%, the reaction mixture was cooled to around room temperature. Generally, the reaction requires about 10 hours. After pH was adjusted to 6.5 with 12 N-NaOH, the solid formed was filtered. The filtered product was washed with 1.0 liter of warm water, and dried under reduced pressure to obtain the title product. m.p. 102°-105° C., amount obtained 676 g, purity 93%, yield 93%.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[N:6]([CH3:31])[C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)n(C)c2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (200 mg, 0.46 mmol), K2CO3 (95 mg, 0.69 mmol), MeI (85 mg, 0.60 mmol) and DMF (2 ml) were stirred at 60° C. for 2 hours. Reaction mixture was cooled, diluted with water (10 ml) and extracted with ethyl acetate (2×5 ml). The organic layer was washed with brine (2×10 ml), dried over Na2SO4 and evaporated to obtain 2-Chloro-7-methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (120 mg, 58%)
Reaction SMILES: [C:1]1([C@H:7]([NH:37][C:38]([O:40][C@@H:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[O:39])[C:8]2[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=2)[O:11][CH2:12][C:13]2[CH:33]=[CH:32][C:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]4OCC[O:28]4)[CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1.C(OCC)(=O)C>[C:1]1([C@H:7]([NH:37][C:38]([O:40][C@@H:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[O:39])[C:8]2[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=2)[O:11][CH2:12][C:13]2[CH:33]=[CH:32][C:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)OCc3cccc(C4OCCO4)c3)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cccc(COC(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(1,3-dioxolan-2-yl)benzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.32 g, 0.57 mmol) in THF (8 mL) was added 2M aqueous hydrochloric acid (8 mL). The reaction mixture was stirred at RT for 1 hour. The mixture was diluted with ethyl acetate and was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine. The organic extract was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used in the next step with no further purification.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=O)[CH2:2][CH3:3].C(Cl)(=O)[C:12]([Cl:14])=O.[N+](=C)=[N-].Cl.O1CCOCC1>ClCCl.CN(C=O)C>[Cl:14][CH2:12][C:5](=[O:7])[CH:4]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(CCC)C(=O)O
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)CCl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 2-propylpentanoic acid (156.6 μl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 μL, 4 mole %), and the solution was cooled to 0° C. under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 μL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0° C. and excess ~0.3M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2mL) and cooled to 0° C. under a nitrogen atmosphere. Hydrogen chloride as a 4N solution in dioxane (275 μL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:5]([NH:7][C:8](OC(C)(C)C)=O)[CH:6]=1.CN(C(OC)OC)C>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]2[C:15]([OH:22])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[N:7][N:5]2[CH:6]=1
Reactant: CCOC(=O)CC(=O)c1nc(Br)cn1NC(=O)OC(C)(C)C
Agent: COC(OC)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnn2cc(Br)nc2c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-(4-bromo-1-((tert-butoxycarbonyl)amino)-1H-imidazol-2-yl)-3-oxopropanoate (1.354 g, 3.60 mmol) in DCM (23.99 ml) at room temperature was added DMF-DMA (1.446 ml, 10.80 mmol). The reaction was stirred at room temperature for 3 h. The resulting yellow suspension was concentrated under reduced pressure to give the crude cyclization product as a yellow oil. A small amount of material was triturated in CH3CN to give a pure sample of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate as a white solid. LCMS (Method B) m/z 288.0 [M+1], Br-pattern; 1H NMR (400 MHz, MeOD) δ 8.39 (s, 1H), 7.62 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:17]2[O:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O.C(Cl)(Cl)Cl>[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][O:7][C:8]3[C:17]4[O:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13](=[O:23])[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:37][CH:36]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc(=O)c2cccc(O)c2o1
Reactant: ClCc1ccc(OCCCCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2cccc(OCc3ccc(OCCCCc4ccccc4)cc3)c2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
A solution of potassium carbonate (330 mg, 2.39 mmol) in dry N,N-dimethylformamide (15 ml) was added with ethyl 8-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (520 mg, 2.39 mmol) stirring at room temperature for 10 min. After that the reaction mixture was added with 4-(4-phenylbutoxy)benzyl chloride 595 mg, 2.17 mmol) and left under stirring at 60° C. for 18 h, subsequently was added with water (25 ml), extracted with ethyl ether (3×50 ml), dried and the solvent was evaporated off under reduced pressure, to obtain a residue which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 7:3, recovering 740 mg of the title compound (66% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[C:33]4[O:32][C:31]([F:35])([F:34])[O:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])C)[CH:17]=[CH:16][C:15]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH2:40](Br)[CH3:41].[ClH:43]>C(O)(C)C>[ClH:43].[CH2:40]([N:20]([C:18]1[CH:17]=[CH:16][C:15]([O:36][CH3:37])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1)[S:22]([C:25]1[C:33]2[O:32][C:31]([F:35])([F:34])[O:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH3:41]
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCN(c1ccc(OC)c(N2CCNCC2)c1)S(=O)(=O)c1cccc2c1OC(F)(F)O2

Procedure:
The compound was prepared by reaction of 4-{5-[(2,2-difluoro-benzo[1,3]dioxole-4-sulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester with sodium hydride and ethylbromide, and subsequent deprotection of the tert.butoxycarbonyl group with hydrochlorid acid in isopropanol.
Reaction SMILES: C=CC.[H][H].[CH2:6]([SiH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].N#N>C1(C)C=CC=CC=1.CCCCCC>[CH:6]([SiH3:14])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: C=CCCCCCC[SiH3]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C=CC
Product: CCCCCCC=C[SiH3]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 2 L Parr reactor was heated to 70° C. and charged with 270 g of propylene and pressured with 0.14 L of hydrogen. 7-Octenylsilane (containing about 14.6 percent of 6-octenylsilane) 0.13 wt percent based on total monomer content, dissolved in 0.5 ml of toluene and pressured to 100 psig over the reactor pressure with N2 was charged to the vessel. To the vessel was then added 12 μmoles of the Zr-containing catalyst, slurried in hexane under N2 pressure of 100 psig above the reactor pressure to initiate the polymerization. The polymerization was continued for 30 minutes and resulted in the formation of 45.3 g of octenylsilane modified polypropylene. The polymer had a mwt of 459,000 and a MWD of 3.2. The copolymer contained added LCB as shown by the increase in solution viscosity as a function of increased absolute molecular weight and an increase in the strain-hardening in extensional flow as a function of extension rate when compared to a polypropylene made under comparative conditions. Based on such analysis the octenylsilane-containing polymer has from 0.2 to 0.5 tetrafunctional branch sites/chain.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
3-Cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methyl ester (210.1 mg, 0.63 mmol) and methyl urea (140.5 mg, 1.90 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 3.6 mL, 2.53 mmol). The resulting reaction mixture was then heated under reflux for 64 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate until the solvent passing through the celite showed absence of desired product by thin layer chromatography. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea (42.7 mg, 18%) as a white solid: mp 144-145° C.; EI-HRMS m/e calcd for C17H21F3N2O2S (M+) 374.1276, found 374.1270.
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:48]=[O:49].O>O1CCCC1.C(OCC)(=O)C>[CH2:37]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][C:16]([CH:48]=[O:49])=[CH:17][CH:18]=2)=[C:8]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CN(C)C=O
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: -71.5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
In a stream of argon, in 25 ml of tetrahydrofuran was dissolved 2.32 g (4.09 mmol) of dibutyl[3-(tert-butyldiphenylsiloxy)-4-[2-(thiophene-2-yl)vinyl]phenyl]amine, and 3.8 ml of n-butyllithium (1.6 mol solution in hexane) (6.08 mmol) was added dropwise thereto under cooling at −70 to −73° C. After the mixture was stirred for 1 hour, 0.4 ml (5.77 mmol) of N,N-dimethylformamide was added dropwise. The reaction mixture was stirred for 1 hour and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 200 ml of ether and 100 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 1.99 g of a dark red oily matter (yield: 81.9%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:13][NH2:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH3:2][C:3]1([CH2:13][NH:14][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC1(CN)CCCc2ccccc21
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: CC1(CNc2cnccc2C(=O)O)CCCc2ccccc21
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from 1-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.24 (br s, 1H), 8.31 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.48 (d, 1H, J=5.0 Hz), 7.45 (br s, 1H), 7.42 (d, 1H, J=7.3 Hz), 7.05-7.15 (m, 3H), 3.44-3.57 (m, 2H), 2.72 (t, 2H, J=6.4 Hz), 1.59-1.92 (m, 4H), 1.32 (s, 3H). [M+H] calc'd for C18H20N2O2, 297. Found 297.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][NH2:19])=[CH:13][CH:12]=1.O>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][N:19]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:15][CH:16]=1
Reactant: CC(C)C(CN)c1ccc(Cl)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(CN=C(O)/C(Cl)=C(/Cl)C(=O)O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 58.1 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 19.7 g (0.1 mol) of 2-(4-chlorophenyl)-3-methylbutylamine are stirred in 100 ml glacial acetic acid at 120° C. for 4 hours. The mixture is cooled to 20° C. and 10 ml of water are added. A colorless precipitate separates out, and is filtered off with suction and dried. 21.2 g of dichloromaleic acid N-[2-(4-chlorophenyl)-3-methylbutyl]imide of melting point 91°-92° C. are obtained. A further 10.4 g of imide can also be isolated by stirring the mother liquor with water. The total yield is: 91.3% of theory.
Reaction SMILES: C1([C@H](NC([C:13]2[CH:14]=[C:15]([C:22](N3CCC[C@@H]3C(O)=O)=[O:23])[N:16]3CCOC[C:17]=23)=O)CC)C=CC=CC=1.[CH:32]([OH:35])([CH3:34])[CH3:33]>Cl>[CH:32]([O:35][C:22]([CH:15]1[CH2:14][CH2:13][CH2:17][NH:16]1)=[O:23])([CH3:34])[CH3:33]
Reactant: CC(C)O
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(=O)O)n2c1COCC2)c1ccccc1
Agent: Cl
Product: CC(C)OC(=O)C1CCCN1

Procedure:
A solution of (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid in isopropanol and 2 drops of concentrated aqueous hydrochloric acid was heated to reflux overnight. Solvents were evaporated. The residue was dissolved in a small amount of acetonitrile, excess water was added and the solution was freeze-dried to give 27 mg (49%) of (R)-1-[84(R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid isopropyl ester. LC/MS (method 4): Rt=1.27 min; m/z=468.35 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: NC(=O)/C=C\c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 1.75 h
Yield: 85 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (12.2 mg, 0.033 mmol), 0.005 mL quinoline, and 4 mg Lindlar catalyst in 1.5 mL EtOAc was reacted under a balloon of hydrogen. After 1.75 hours, an additional catalytic amount of Lindlar catalyst was added and the reaction continued for an additional 1 hour. The reaction mixture was partitioned between EtOAc and dilute aqueous HCl, the EtOAc layer washed with H2O, brine, dried with Na2SO4 and evaporated. The crude material was chromatographed eluting with hexane/acetone to give the title compound as a white solid (10.3 mg, 84%). 1H NMR (Acetone-d6) δ: 8.79 (d, J=7.9 Hz, 1H), 8.69 (br. s., 1H), 8.37 (br. s., 1H), 7.75 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.35-7.43 (m, 2H), 6.93 (br. s., 1H), 6.64 (d, J=12.9 Hz, 1H), 6.41 (br. s., 1H), 5.97 (d, J=12.9 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[N:38]1([C:44]2[N:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:50]([C:47]2[CH:48]=[N:49][C:44]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:45][CH:46]=2)(=[O:52])=[O:51])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1CN(S(=O)(=O)c2ccc(N3CCOCC3)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35.6 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (35.4 mg, 0.084 mmol) in CH2Cl2 (3 mL) was added DIPEA (44.5 mg, 0.344 mmol) and 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (45.0 mg, 0.171 mmol, Maybridge). It was stirred at rt for 3.5 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (18.7 mg, 0.071 mmol, Maybridge) were added. After 1.75 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(6-morpholin-4-yl-pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile (19.4 mg, 35.7%). HRMS (ES+) m/z Calcd for C31H32Cl2F2N4O3S H [(M+H)+]: 649.1613; Found: 649.1615.