Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][C:49]=1[CH3:56]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:52][C:51]4[CH:54]=[CH:55][C:48]([F:47])=[C:49]([CH3:56])[CH:50]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CN)ccc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(F)c(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-fluoro-3-methylbenzylamine (Matrix) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=O)[CH:3]=1.[Cl-].C[NH3+].[C:21]([BH3-])#[N:22].[Na+]>CO>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][NH:22][CH3:21])[CH:3]=1
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reactant: [BH3-]C#N
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120 %

Procedure:
To a solution (60 mL) of 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.5 g) in methanol were added methylammonium chloride (7.5 g) and sodium cyanoborohydride (2.4 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 4.4 g, about 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C1C=CC=CC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CC1C=CC=CC=1C>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(-n2ccnc2)cc1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
Tert-butyl 2-(4-bromophenyl)ethylcarbamate (500 mg, 1.67 mmol), imidazole (170 mg, 2.50 mmol), (CuOTf)2.PhH (84 mg, 0.17 mmol), 1,10-Phenanthroline (360 mg, 2.00 mmol), dba (39 mg, 0.17 mmol), and Cs2CO3 (650 mg, 1.99 mmol) were mixed together in a flask and o-xylene (10 mL) was added. Resulting solution was heated to 120° C. and stirred for four days. Reaction mixture was then cooled, poured into water (20 mL) and extracted with EtOAc (3×20 mL). Combined organics were washed with water (1×20 mL) and brine (2×20 mL), dried over sodium sulfate, filtered, and concentrated Crude product was purified by flash chromatography eluting with 25% Hexanes in EtOAC to pure EtOAc to give tert-butyl 2-[4-(1H-imidazol-1-yl)phenyl]ethylcarbamate.
Reaction SMILES: [F:1][C:2]([F:13])([CH:10]([F:12])[F:11])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O>[F:1][C:2]([F:13])([CH:10]([F:11])[F:12])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C/C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl (E)-4,4,5,5-tetrafluoropent-2-enoate (15.9 g, 0.08 mol) was dissolved in ethanol (30 ml), 4M NaOH was added (15 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with water, washed with ethylacetate, acidified with 1M HCl and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, the solvent was removed under reduced pressure. 12.8 g of a colourless oil was obtained (0.074 mmol, 93%). MS (ESI, negative detection) m/z=170.9 [M−1]−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22](=[O:25])[CH:21]=[C:20]2[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:16]([O:35][CH3:36])=[CH:17][CH:18]=2)[O:23][C:22](=[O:25])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCN(C)CC1
Reaction time: 10 h

Procedure:
1-Methylpiperazine (0.2 mL, 1.8 mmol) was added to a solution of 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (50 mg, 0.1 mmol, Example 28) and DMSO (1.5 mL). After 10 h, the reaction was poured into 10% K2CO3 (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried, filtered, concentrated, and purified by reverse-phase HPLC (acetonitrile:water) to give 4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(5-(4-methylpiperazin-1-yl)pentyloxy)-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.45 (br s, 1H), 8.71 (s, 2H), 7.90 (d, 1H), 7.13 (d, 1H), 4.46 (br s, 1H), 3.97 (t, 2H), 3.90 (s, 3H), 2.60-2.20 (br, 10H), 2.21 (s, 3H), 1.68 (m, 2H), 1.47 (m, 4H); MS (ESI): 520.9.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][OH:13]>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: Cc1cccc(OCCO)c1
Product: Cc1cccc(OCCOS(N)(=O)=O)c1
Yield: 47 %

Procedure:
The title compound was prepared by procedures of Example 4 from sulfamoyl chloride and 2-(3-methylphenoxy)ethanol in 47% yield [recrystallizing ethyl ether-petroleum ether (30°-60° C.)]. A white solid, mp 76°-78° C., was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33](CCl)=[CH:32][CH:31]=1)(=[O:28])[CH3:27]>>[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Oc1ccc(CCl)cc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(=O)Oc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-(chloromethyl)phenyl acetate to give 6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32][C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:30][CH:31]=3)=[N:20][O:21]C(C)(OC)C)[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(NCC)C.Cl>CC(C)=O>[C:1]([S:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32][C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[S:30][CH:31]=3)=[N:20][OH:21])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CCNCC
Solvent: CC(C)=O
Product: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1

Procedure:
The product of Step A was added to a mixture of 10 ml of acetone and 3.5 ml of 2N hydrochloric acid and the acetone was evaporated. The mixture was extracted with ethyl acetate and the ethyl acetate phase was triturated with ether. The mixture was vacuum filtered to obtain the syn isomer of 3-acetylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid which was then stirred with 4 ml of aqueous formic acid (1 volume water - 2 volumes of formic acid) at 45° C. for 10 minutes. The mixture was evaporated to dryness under reduced pressure and the residue was triturated with 5 ml of water. The mixture was vacuum filtered and dried under reduced pressure to obtain 1 g of raw product which was dissolved in 20 ml of ethanol. The mixture was vacuum filtered to remove insolubles and the filtrate was evaporated to half its volume. 20 ml of ethanol were added thereto and the mixture was again evaporated to half its volume. The mixture was vacuum filtered and the product was washed with ethanol and with ether to obtain 0.5 g of purified syn isomer of 3-acetylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]([CH3:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O.S(=O)(=O)(O)O.[OH-].[Na+]>ClCCl>[Cl:20][C:18]1[CH:17]=[C:16]2[C:3](=[C:2]([Cl:1])[CH:19]=1)[CH2:4][N:5]([CH3:15])[CH2:6][CH:7]2[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Temperature: 0 °C
Yield: 49.8 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-phenylethanol (3.4 g, 11.00 mmol, 1.00 equiv) in dichloromethane (15 mL). This was followed by the addition of sulfuric acid (15 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The pH value of the solution was adjusted to 7 with 1M sodium hydroxide. The resulting solution was extracted with ethyl acetate (3×60 mL) and the combined organic layers dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether:ethyl acetate (80:1). This resulted in 1.6 g (50%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=3[C:13]=2[CH2:14][O:15][CH3:16])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=3[C:13]=2[CH2:14][O:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCc1c(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a mixture of cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methanone (857 mg) synthesized above, methyl 4-aminobenzoate (491 mg), triethylamine (3.29 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (388 μL), and the mixture was stirred under argon atmosphere at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (847 μL) and sodium cyanoborohydride (371 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (454 mg, 36%) as a pale-brown oil
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].ClC(OCC)=O.[BH4-].[Na+].CO>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COC(=O)CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCCCCO
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Azelaic acid monomethyl ester (20 mmole) was dissolved in tetrahydrofuran (100 mL) and kept in argon atmosphere at −10° C. Trietbylamine (30 mmole) was added dropwise to the reaction flask, followed by the addition of ethyl chloroformate (25 mmole). The solution was stirred for 20 minutes, and sodium borohydride (60 mmole) was added in one portion. Methanol (40 mL) was added dropwise and the reaction flask was kept at 0° C. for 40 minutes. Water (20 mL) was added and organic solvent was removed by rotavap. The residue was brought to water and ethyl acetate for partition. The organic layer was collected and dried to obtain 9-hydroxy-nonanoic acid methyl ester in decent purity for use in Step 4. The yield is >90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-N-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (5.4 g, 19.4 mmol) in methanol (150 mL) at 0° C. was added a solution of hydrochloric acid in p-dioxane (4.0 M in p-dioxane, 19.4 mL, 77.6 mmol). The reaction was slowly warmed to room temperature and stirred at room temperature for 18 h. The solvent removed in vacuo, and the crude material was dissolved in saturated aqueous sodium bicarbonate and dichloromethane. The mixture was stirred for 45 min to give a clear solution. The phases were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (3.1 g, 92%, >96% ee, determined by Mosher's method).
Reaction SMILES: [CH2:1]([O:4][C:5]([F:14])([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7])[CH:2]=[CH2:3].F[C:16](F)(F)C(C(F)(F)F)=O.[F-].[K+].C(Cl)C(=C)C>CN(C)C=O>[CH2:1]([O:4][C:5]([F:14])([C:10]([F:11])([F:12])[F:13])[C:6]([F:7])([F:8])[F:9])[C:2](=[CH2:16])[CH3:3]
Reactant: C=CCOC(F)(C(F)(F)F)C(F)(F)F
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: C=C(C)CCl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COC(F)(C(F)(F)F)C(F)(F)F
Yield: 85 %

Procedure:
this compound was prepared in a manner analogous to that used for the allyl ether (Example 1), using hexafluoroacetone, anhydrous KF, dimethylformamide, and methallyl chloride. Heptafluoroisopropyl methallyl ether was obtained in 85% yield, b.p. 82° C./760 mm., nD25 1.3129.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10].O.[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1.O>C1C=CC=CC=1.CC(C)=O>[CH3:15][C:14]1([CH3:19])[O:10][CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:11][O:12]1
Reactant: OCC(CO)CCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(CCCCCCBr)CO1

Procedure:
24.2 g of crude 2-(6-bromohexyl)-1,3-propanediol was dissolved in a mixture of 200 mL of benzene, 30 mL acetone, and 0.4 g toluene-4-sulfonic acid monohydrate (Fluka, puriss.) in a 1 L 1-necked round flask. While magnetically stirring and refluxing 1.4 mL of water was separated and collected in a Dean-Stark trap during 22 h. The solvents were removed by rotary evaporation under reduced pressure and the residue vacuum distilled to recover 14.65 g of 2,2-dimethyl-5-(6-bromohexyl)-m-dioxane with b.p. 96°-97° C./0.06 mbar.
Reaction SMILES: COC1C=C(C[C:21]([OH:23])=[O:22])C=CC=1NC(NC1C=CC=CC=1C)=O.[CH:24]1[CH:25]=[CH:26][C:27]2N(O)N=N[C:28]=2[CH:29]=1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:21]([OH:23])(=[O:22])[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:29]=1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of ethyl 4-(2-allylaminoethoxy)-3-methoxy benzoate (578 mg, 2.1 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylaceticacid (650 mg, 2.1 mmol), HOBt (420 mg, 3.11 mmol), and DMAP (catalytic amount) in DMF (4 mL) was added EDC (596 mg, 3.11 mmol) at room temp. The resulting mixture was stirred for a further 18 hr at room temp. The mixture was poured into 1N HCl and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on silica-gel with CHCl3:EtOAc (95:5 to 1:1, v/v) as eluent to give 1 g (84%) 3-methoxy-4-[[2-3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]allylamino]ethoxy]benzoic acid as a pale-yellow gum. 1H-NMR (CDCl3, 400 MHz) δ1.39 (t, 3H, J=7.3 Hz), 2.29 (s, 3H), 3.58 and 3.63 (s, total 3H), 3.70-3.77 (m, 2H), 3.83 and 3.87 (s, 3H), 4.054.13 (m, 2H), 4.25 (m, 1H), 4.36 (q, 1H, J=7.0 Hz), 5.04-5.22 (m, 2H), 5.73 (m, 1H), 6.32 and 6.47 (s, 1H), 6.69-6.85 (m, 2H, 7.12 (m, 2H), 7.23 (m, 2H), 7.50-7.65 (m, 2H), 8.05 (d, 1H, J=7.8 Hz); MS (FAB) m/z 576(M+H)30.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[OH:13].[Br:14]Br>C(O)(=O)C>[Br:14][C:4]1[C:3]([OH:13])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2
Reactant: BrBr
Reactant: Cc1ccc2cc(O)c(Cl)cc2n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.1 %

Procedure:
To a stirred solution of 7-chloro-2-methylquinolin-6-ol (1C) (450 mg, 2.3 mmol) in acetic acid (15 mL) was added Br2 (0.13 mL, 2.4 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 hours. The solid that formed was filtered and collected to give 1D as an off-white solid as the HBr salt (847 mg, 100%). LCMS-ESI+ (m/z): 281.1, 283.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:10]1[O:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>C(O)(C)C>[OH:12][C@H:10]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:24][CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: CC(C)CN
Solvent: CC(C)O
Product: CC(C)CNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 3(S)-(t-butyloxycarbonyl)amino-1,2(S)-epoxy-4-phenylbutane (200 mg, 0.76 mmol) in 2 mL of dry isopropanol was added isobutylamine (0.38 mL, 3.8 mmol) and the mixture was stirred for 5 h at 50° C. The mixture was concentrated under reduced pressure and dried in vaccuo to give 230 mg of 2(S)-hydroxy-3(S)-(t-butyloxycarbonyl)amino-1-isobutylamino-4-phenylbutane
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([Cl:10])[CH:4]=1.C[Si]([C:15]#[N:16])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: N#CCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 4-bromomethyl-2-chloro-1-fluoro-benzene (3.7 g, 16.5 mmol) in CH3CN (30 mL) was added trimethylsilyl cyanide (2.1 mL) and TBAF (4.8 g, 18.4 mmol). The resulting mixture was heated at reflux for 30 min. After cooling of the mixture to room temperature, it was extracted with EtOAc. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel flash column chromatography to give the title compound (1.7 g, 60.7%) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][NH:24][CH2:23][CH2:22][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH3:26][N:27]1[C:31]([S:32](Cl)(=[O:34])=[O:33])=[CH:30][CH:29]=[N:28]1>>[OH:1][CH:2]1[CH2:25][N:24]([S:32]([C:31]2[N:27]([CH3:26])[N:28]=[CH:29][CH:30]=2)(=[O:34])=[O:33])[CH2:23][CH2:22][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2
Reactant: Cn1nccc1S(=O)(=O)Cl
Reactant: CC(Oc1ccc(N2CCC3(CCNCC3O)C2=O)cc1)C(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccnn4C)CC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-((rac)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 10 step B) and 2-methyl-2H-pyrazole-3-sulfonyl chloride. Light yellow solid. MS (ESI): 503.1 (MH+)
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3].Br[CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25]>>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCCn1c(=O)c2[nH]cnc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(ncn2CCCP(=O)(OCC)OCC)n(CCC)c1=O

Procedure:
The title substance was prepared from 1,3-dipropylxanthine and diethyl 3-bromopropanephosphonate analogously to Example 1 and chromatographed on silica gel (eluent: ethyl acetate/methanol 20:1).