Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[F:34][C:35]([F:49])([F:48])[C@:36]([O:46][CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:37](=[O:38])[C@@:36]([O:46][CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:35]([F:48])([F:49])[F:34])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@](C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To racemic 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (obtained as described in Example 1, Procedure 1) (55 mg, 0.14 mmol) in DCM (1 mL) was added pyridine (56 μL, 55 mmol) and (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (52 μL, 0.22 mmol). The reaction was stirred at room temperature for 14 h and the reaction mixture filtered through a silica plug elution with DCM. (S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide was crystallized from ether heptane.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cccc(Br)n2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 6-bromo-pyridine-2-carboxylic acid and 1-methyl-piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1C(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 30 ml of N,N-dimethylformamide was dissolved 5.0 g of 2-amino-5-chloro-2'-hydroxybenzophenone, as obtained in Example 123 (1), to which were added 4.2 g of potassium carbonate and 2.9 ml of benzyl bromide; the mixture was then stirred for 2 hours at room temperature. The mixture was subjected to extraction with 150 ml of water and 200 ml of ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (eluent, hexane:ethyl acetate=10:1 to 5:1) to yield 6.4 g of 2-amino-2'-benzyloxy-5-chlorobenzophenone as prism crystals, m.p. 110° to 111° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[N:13][C:12]=2[CH:16]=1>>[CH3:6][O:7][C:8]1[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:12]2[N:13]=[N:14][S:15][C:11]2=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2snnc2c1
Product: COc1ccc2snnc2c1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 50 mL of chlorosulfonic acid at 0° C. was added 4.15 g of 5-methoxy-1,2,3-benzothiadiazole under an inert atmosphere. The resulting mixture was heated at reflux for 30 minutes. After cooling to room temperature, the reaction mixture was added to 600 mL ice-water mixture. The precipitate was collected, washed with water and ether, and air dried to give 5.6 g of the title compound as a white solid, m.p. 131°-134° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(N)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(Oc2ccc(NS(C)(=O)=O)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-(4-amino-2-{[methoxycarbonyl-((S)-1-methyl-2-phenyl-ethyl)-amino]-methyl}-phenoxy)-phenyl]-acetic acid ethyl ester (0.144 g, 0.3 mmol) and methanesulfonyl chloride (0.02 mL, 0.3 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.08 mL, 0.6 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was worked-up with CH2Cl2 and H2O, and the organic layer was dried and concentrated. The residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:28])([F:27])[C:11]([N:13]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]>CCOCC>[F:9][C:10]([F:28])([F:27])[C:11]([N:13]([CH2:20][P:21]([O:25][NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:23][NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: NNc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONNc1ccccc1)ONNc1ccccc1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To a solution of phenylhydrazine (4.5 g, 0.0423 mole) in 40 ml. of ether was added dropwise with good stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) dissolved in ether. The reaction was stirred at room temperature for two hours, then filtered and the filtrate concentrated in vacuo to give a gum-solid. This was triturated with petroleum ether, then ether. The ether insoluble solid was washed with water to give ethyl N-trifluoroacetyl-N-(bis(phenylhydrazino)phosphonomethyl)glycinate (0.6 g), m.p. 113°-116° C. (glass), 143°-145° C. with decomposition.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH:25]=2)[N:16]=1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH3:8].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH:25]=2)[N:16]=1
Reactant: CC(Nc1cc(-n2nc(N3CC4CC3CN4C(=O)OC(C)(C)C)c3ccccc32)ccn1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(-n2nc(N3C[C@@H]4C[C@H]3CN4)c3ccccc32)ccn1)c1ccccc1
Product: N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To the 5-{1-[2-(1-phenyl-ethylamino)-pyridin-4-yl]-1H-indazol-3-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.044 g, 0.086 mmol) were added 4N HCl in dioxane (1 mL) and a few drops of methanol. After stirring at room temperature for 30 min, the reaction was concentrated in vacuo and the residue was partitioned between methylene chloride and saturated sodium bicarbonate; the aqueous layer was back-extracted with methylene chloride (2×). The combined organic extract was dried (K2CO3), filtered, and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% 2M NH3 in MeOH/CHCl3 gave the title compound as a cream colored solid. MS (ES+): 411.3 [M+H]+, 409.5 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[C:42]([CH2:46][NH2:47])[CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([NH:47][CH2:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([O:33][C:32]([F:31])([F:48])[F:49])=[CH:35][CH:36]=3)[CH:41]=2)=[O:9])[CH2:5][CH2:6]1)[CH3:2]
Reactant: NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
A solution of acid 15A (0.30 g, 1.8 mmol) in THF (20 mL) was added with DEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 10 minutes. Then [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.308 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (45 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over an. Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a white solid (0.15 g). Yield=28%, 1HNMR (DMSO, 200 MHz) δ 1.08 (m, 2H), 1.20 (t, 3H, J=8), 1.38 (bs, 2H), 3.42 (q, 2H), 4.38 (d, 2H, J=5.6), 7.27 (d, 1H, J=4), 7.46-7.39 (m, 6H), 7.55 (d, 1H), 7.59 (s, 1H), 7.78 (m, 2H), 7.87 (m, 2H), 8.08 (t, 1H). [M+1] 536.54 (C26H24F4N2O4S requires 536.14).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:14])(=[O:13])[C:10](C)=[CH2:11].[CH3:15][O:16][CH2:17]CO.[OH2:20]>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([O:16][CH3:15])(=[O:20])/[CH:11]=[CH:10]\[C:9]([O-:14])=[O:13]
Reactant: COCCO
Reactant: O
Reactant: C=C(C)C(=O)O
Solvent: C=Cc1ccccc1
Product: COC(=O)/C=C\C(=O)[O-]

Procedure:
In the case of a solution polymerization, for example, 23 parts of styrene, 24 parts of methacrylic butyl, 23 parts of methacrylic acid, and 10 parts of a polyethylene glycol monomethyl ester of methacrylic acid are fed in water-soluble solvent (e.g., butyl cellosolve) at 80 to 140° C. under an ambient nitrogen atmosphere, and are pre-mixed. The mixture is then copolymerized for 4 to 5 hours with dripping a polymerization initiator, then 20 parts of the AD copolymer (e.g., obtained from 10 parts of styrene and 10 parts of monomethyl maleate) is added to the mixture, and is heated and stirred for 2 to 8 hours.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].[C:14](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(F)c(C)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1c(C(C)=O)cc(F)c(C)c1Br
Temperature: 60 °C
Yield: 91.9 %

Procedure:
To a mixture of 1-(3-bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone (0.3 g, 1 mmol) and potassium carbonate (0.43 g, 3.1 mmol) was added N,N-dimethylformamide (1 mL) and methyl iodide (0.17 mL, 2.7 mmol) with stirring. The resulting mixture was then heated at 60° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated to dryness. The isolated residue was purified on silica gel, eluting with ethyl acetate/hexanes (0 to 20%) to yield 1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone (0.24 g, 80%). LCMS calculated for C10H11BrFO2 (M+H)+: m/z=261.0, 263.0. Found: 260.9, 262.9. 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 1H), 3.82 (s, 3H), 2.61 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: C(C(C)=[O:4])=C.Cl[CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15].[C-:17]#[N:18].[Na+:19]>C(O)C>[C:17]([CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])#[N:18].[OH-:4].[Na+:19]
Reactant: [C-]#N
Reactant: CC(=O)CCC#CCCCCl
Reactant: C=CC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)CCC#CCCCC#N
Product: [OH-]

Procedure:
The manufacture of the latter novel intermediates is exemplified by the consecutive synthetic steps involving first, reaction of 5-chloropent-1-yne with butyl lithium to form the corresponding lithium acetylide, reaction of that organometallic compound with boron trifluoride or boron trichloride to afford the tri-(5-chloropent-1-ynyl) boron derivative, which is reacted with methyl vinyl ketone to afford 9-chloro-5-nonyn-2-one, reaction of the latter substance with sodium cyanide in aqueous ethanol to yield 9-cyano-5-nonyn-2-one, saponification of that nitrile with aqueous sodium hydroxide in ethanol to produce 9-oxo-5-decynoic acid, followed by reduction of the olefinic double bond, thus affording the 9-oxo-5-decenoic acids. The cis-acid is conveniently produced by catalytic hydrogenation, e.g. with a palladium-on-barium sulfate catalyst in the presence of a catalyst poison such as quinoline, while the trans-acid is obtained by chemical reduction, e.g. with sodium and liquid ammonia.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:12]=[CH:13][C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CC#N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Yield: 96 %

Procedure:
A mixture of sodium ethoxide prepared from sodium metal (415 mg) and ethanol (20 ml), 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetonitrile (4.7 g) and diethyl carbonate (7.8 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetate (5.7 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>C1C=CC=CC=1.CCO.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:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Solvent: c1ccccc1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 4b (1.0 g, 1.79 mmol) in benzene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine)palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 4c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+-Boc).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8](N(CC)CC)C.C[C:16](=O)[CH2:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CC(O)=O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][CH2:8][CH:17]([CH3:16])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CCC(C)=O
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CNCC(C)C
Yield: 27.9 %

Procedure:
Glycine methylester hydrochloride (2.0 g, 16.0 mmol) was dissolved in MeOH/AcOH (9:1, 25 ml). Triethylamine (1.8 g, 18.0 mmol) was added followed by 2-butanone (1.3 g, 18.0 mmol). After 2 h at room temperature sodium triacetoxyborohydride (3.81 g, 18.0 mmol) was added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (200 ml). This solution was washed with sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (646 mg, 4.46 mmol, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28](N(CC)CC)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:26])([F:25])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH:17][CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: ClCCl
Product: CNc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in DCM (10 mL) was added triethylamine (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at RT for 18 h. The DCM layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[N+:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Yield: 49.1 %

Procedure:
The compound was prepared from tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 2.8 g (49%) of the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (d, J=7.03 Hz, 9H) 2.26-2.38 (m, 2H) 3.55-3.81 (m, 4H) 5.20 (br s, 1H) 6.77 (d, J=8.53 Hz, 1H) 7.59 (t, J=7.53 Hz, 1H) 7.72-7.76 (m, 1H) 8.32 (d, J=8.03 Hz, 1H) 8.37 (d, J=8.53 Hz, 1H) 8.76 (d, J=8.53 Hz, 1H). HPLC 95%, RT=2.775 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17](SC)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:33]([O-:38])(O[O-])(=O)=[O:34].[K+].[K+].O.[C:42](#N)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[N:18]=[C:17]([S:33]([CH3:42])(=[O:38])=[O:34])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CC#N
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1

Procedure:
4-[2-Methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (185 mg) and potassium peroxymonosulfate (558 mg) were stirred at room temperature in acetonitrile (3 ml) and water (300 μl) for eight hours. Reaction mixture was then diluted with ethyl acetate (50 ml) and washed with water (2×40 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated under reduced pressure to yield product 4-[2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (139 mg) as a yellow gum. MS m/z 501.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:21]([O-:24])(=[O:23])=O)[C:5]2[C:10]([C:11]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH+:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:26]([N:25]([CH2:30][CH3:29])[S:21]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]2[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:1][C:2]=2[CH:3]=1)(=[O:24])=[O:23])[CH3:27]
Reactant: c1cc[nH+]cc1
Reactant: O=C(Nc1c(O)cc(S(=O)(=O)[O-])c2ccccc12)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1cc2oc(-c3ccccc3)nc2c2ccccc12
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A mixture of 3.43 g pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate and 10 ml thionyl chloride was refluxed for 3.5 hours. Toluene (20 ml) was added and the excess thionyl chloride was distilled off with toluene under reduced pressure. The solid residue was dissolved in 50 ml methylene chloride and 10 ml diethylamine was added portionwise while stirring. After 30 min, the reaction mixture was poured into 100 ml ice-water and extracted with 100 ml dichloromethane. The organic phase was separated, washed with water, and dried over sodium sulfate. Evaporation of the solvent gave 2.52 g N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide of high purity by NMR. Recrystallization from 95% ethanol gave an analytical sample, m.p. 157° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.C(N(CC)CC)C.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32].C1(C)C=CC=CC=1>ClCCl>[CH2:31]([NH:33][C:34]([N:10]1[C:11]2[C:6](=[CH:5][C:4]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C:3]=3[C:2]=2[CH3:1])[CH2:7][CH2:8][CH2:9]1)=[O:35])[CH3:32]
Reactant: Cc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCNC(=O)N1CCCc2cc3c(c(C)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 167 mg of t-butyl 11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of dichloromethane were added 0.221 ml of triethylamine and 0.062 ml of ethyl isocyanate, followed by stirring at room temperature for 15 hours. To the reaction mixture were added 3 ml of toluene and 0.062 ml of ethyl isocyanate, followed by heating to 60° C. and stirring for 15 hours. Then, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 200 mg of t-butyl 1-(ethylcarbamoyl)-11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless viscous substance.