Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[OH:20])[CH2:14][CH2:13]1.[OH:30][CH:31]([CH:35]([OH:39])[C:36]([OH:38])=[O:37])[C:32]([OH:34])=[O:33]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:20])[CH2:16][CH2:17]1.[OH:30][CH:31]([CH:35]([OH:39])[C:36]([O-:38])=[O:37])[C:32]([O-:34])=[O:33]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: OC(COc1ccc(F)cc1)CN1CCC(NCc2nc3ccccc3s2)CC1
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
To a stirred solution of 5 parts of 4-[(2-benzothiazolyl)methylamino]-α-[(4-fluorophenoxy)methyl]-1-piperidineethanol in 80 parts of ethanol were added 1.8 parts of (+)-[R-(R*,R*)]-2,3-dihydroxybutanedioic acid while boiling. The product was allowed to crystallize. It was filtered off and dried, yielding 5.5 parts (94%) of (+)-4-[(2-benzothiazolyl)methylamino]-α-[(4-fluorophenoxy)-methyl]-1-piperidineethanol [R-(R*,R*)]-2,3-dihydroxybutanedioate (2:1); mp. 189.1° C. (457).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(S(N2C3N=CN=C([Cl:35])C=3C(I)=C2)(=O)=O)C=CC=CC=1.BrC1C=C(B(O)O)C=CC=1.[Br:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>CO>[Br:47][C:48]1[CH:49]=[C:50]([NH:51][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([Cl:35])=[CH:13][CH:12]=4)=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ncnc21
Reactant: Clc1ncnc2[nH]cc(-c3ccccc3)c12
Agent: OB(O)c1cccc(Br)c1
Solvent: CO
Product: Clc1ccc(-c2c[nH]c3ncnc(Nc4cccc(Br)c4)c23)cc1
Yield: 75 %

Procedure:
Utilizing an analogous procedure as described in Example 26, 4-chloro-(5-phenyl)-7H-pyrrolo[2,3-d] pyrimidine, the intermediate, was made in 74% yield from 7-benzenesulfonyl-4-chloro-5iodo-7H-pyrrolo[2,3-d]pyrimidine and 3-bromo benzene boronic acid: TS-MS: 230 (MH+) This second intermediate was coupled with 3-bromoaniline in methanol in a sealed tube to provide (3-bromo-phenyl)-[5-(4-chloro-phenyl)7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine in 75% yield: TSMS: 365 (MH+). (3-bromo-phenyl)-[5-(4-chloro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine was brominated with N-bromosuccinimide impregnated onto silica gel. The reaction was complete after stirring at room temperature under nitrogen for 1.5 hours. The reaction was filtered and concentrated in vacuo to provide the title compound as a gray solid in 28% yield (128 mg): MP.: dec 300° C.; TSMS: 445/447 (MH+/MH+2); anal. RP1 8-HPLC RT=7.223 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH2:9])=[O:8].[CH2:10]1[CH:12]([CH:13](O)C#[N:15])[CH2:11]1>>[CH:12]1([CH2:13][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH2:9])=[O:8])[CH2:10][CH2:11]1.[NH3:15]
Reactant: NC(=O)[C@H]1CCCCN1
Reactant: N#CC(O)C1CC1
Product: N
Product: NC(=O)[C@H]1CCCCN1CC1CC1

Procedure:
The title compound was prepared by a similar method to preparation 57 from (2R)-2-piperidinecarboxamide [see preparation 68] and cyclopropylcarboxaldehye. The crude compound was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92:7:1) as the eluant to afford the product as a white solid, (44%).
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N)CN>[Cu]I.O1CCOCC1>[O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Ic1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 40 h
Yield: 45.5 %

Procedure:
To a sealed-vial was added (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (162 mg, 0.756 mmol), potassium phosphate (321 mg, 1.51 mmol), iodobenzene (0.101 mL, 0.907 mmol), ethylenediamine (0.020 mL, 0.30 mmol), dioxane (3 mL) and molecular sieves followed by copper(I) iodide (57.6 mg, 0.302 mmol). The vial was purged with nitrogen gas and sealed. Then the reaction was stirred at 110° C. for 40 hr. The reaction was diluted with EtOAc (30 mL) and washed with water (20 mL) and saturated aqueous NaCl (20 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A) to give (S)-tert-butyl 2-oxo-1-phenylpiperidin-3-ylcarbamate (100 mg, 0.344 mmol, 45.6% yield) as a white solid. Anal. Calcd. for C16H22N2O3 m/z 290.3. found: 291.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.40 (t, J=7.70 Hz, 2H), 7.33-7.20 (m, 3H), 5.56 (br. s., 1H), 4.37-4.20 (m, 1H), 3.78-3.66 (m, 2H), 2.63 (dd, J=12.37, 5.77 Hz, 1H), 2.16-1.97 (m, 2H), 1.81-1.661 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[NH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:20][CH:21]=2)[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][N:4]=1.O1CCC[CH2:29]1.O[O:34][S:35]([O-:37])=O.[K+].C(=O)([O-])O.[Na+]>O.CO>[CH3:29][S:35]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[NH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:20][CH:21]=2)[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][N:4]=1)(=[O:37])=[O:34]
Reactant: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cn1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 2-(methylsulfanyl)-5-[1-(5-(pyridin-2-yl)-1H-pyrrol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl]pyridine (0.365 g) in a mixed solvent of tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL) was added Oxone (registered trade mark, 1.77 g), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.200 g, yield 51%) as colorless crystals. MS: 412 (MH+). melting point 89-90° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C@H:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1)[NH2:16]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][NH:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C@H:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:19][CH:18]=2)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(NN)cc1
Solvent: CCO
Product: COc1c(O)ccc(C=NNc2ccc(C3=NNC(=O)C[C@H]3C)cc2)c1[N+](=O)[O-]

Procedure:
A solution of 4-hydroxy-3-methoxy-2-nitro-benzaldehyde (1.6 g) in ethanol (15 ml) was added to a suspension of (R)-6-(4-hydrazino-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one (1.75 g) in ethanol (20 ml) and the resulting mixture refluxed for two hours. The resulting crystals were filtered at room temperature and washed with ethanol. Yield 2.37 g. HPLC: purity 99.4%, optical purity 99.8%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[N+:23]([O-])=O)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:27][C:28](=[O:50])[CH2:29]N1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O.F[C:52]1[CH:57]=[C:56](C)[CH:55]=[C:54]([CH3:59])[C:53]=1[N+]([O-])=O>>[CH2:59]([O:50][C:28](=[O:27])[CH2:29][N:23]1[C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[NH:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]1=[O:12])[C:54]1[CH:53]=[CH:52][CH:57]=[CH:56][CH:55]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(NC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(F)c1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: Cc1cc(C)c2c(c1)NC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC(=O)OCc1ccccc1
Yield: 93 %

Procedure:
(2S)-2-tert-Butoxycarbonylamino-3-(2-nitro-3,5-dimethylphenylamino)-propionic acid. Prepared by a method similar as described for 600a (Step A), except 2-fluoro-4,6-dimethyl-nitrobenzene was used instead of 2-fluoronitrobenzene to give the desired compound in 93% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:17]>Cl.O>[ClH:17].[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][NH2:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NN)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
To a cooled (-15° C.) and stirred suspension of 4-aminobenzonitrile (50 g, 423 mmol) in concentrated hydrochloric acid (550 ml) was added dropwise a solution of sodium nitrite (31.5 g, 457 mmol) in water (200 ml) at such a rate as to maintain the temperature below -10° C. After the addition was finished, the reaction mixture was quickly filtered to remove solids and the filtrate was added portionwise to a cooled (-20° C.) and stirred solution of tin (II) chloride dihydrate (477 g, 2.1 mol) in concentrated hydrochloric acid (370 ml) at such a rate as to maintain the temperature below -10° C. After further 15 minutes at -10° to 0° C., the white precipitate was collected by filtration, washed with diethyl ether (4×250 ml) and dried to give 56 g (78%) of the title compound; mp 235°-237° C. (ethanol-water 1:1 ); δH (250 MHz, DMSO-d6) 10.50 (3H, br s, --N+H3), 9.10 (1H, br s, --NH--), 7.71 (2H, d, J=8.8 Hz, Ar--H), 7.03 (2H, d, J=8.8 Hz, Ar--H); m/z (CI) 132 (M+ -1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:17]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18]1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH:22][CH2:21][CH2:20][CH:17]2[CH2:19][CH2:18]2)=[O:10])=[CH:4][CH:3]=1
Reactant: NCCC1CC1
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reaction time: 0.5 h

Procedure:
To a suspension of 6-chloropyridazine-3-carboxylic acid (4.1 g, 25.8 mmol) from Step 1 and DMF (50 μL) in CH2Cl2 (60 mL) at r.t. was added oxalyl chloride (5.0 mL, 57.1 mmol) and the mixture was refluxed for 30 min. Volatile materials were removed in vacuo to give the crude acid chloride as a pale yellow solid. The acid chloride was dissolved in CH2Cl2 (40 mL) and added to a solution of cyclopropylethylamine (2.4 g, 28.2 mmol) and Et3N (11 mL, 78 mmol) in CH2Cl2 at 0° C. over a period of about 15 min. After further stirring for 30 min, the mixture was diluted with more CH2Cl2, washed successively with 10% HCl, saturated aqueous NaHCO3, water, dried (Na2SO4) and concentrated. Chromatography over silica gel and elution with hexanes-EtOAc (2:1) gave the title compound as a white powder. 1H NMR (500 MHz, Acetone-d6): δ 0.12 (d, 2H), 0.47 (t, 2H), 0.80 (s, 1H), 1.57-1.61 (m, 2H), 3.58-3.62 (m, 2H), 8.02 (d, 1H), 8.31 (d, 1H), 8.62 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[C@H:4]([O:12][CH3:13])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][O:12][C@@H:4]1[CH2:3][C@@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:7][CH2:6][C@H:5]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CC[C@H](O)C[C@H]1OC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](OS(C)(=O)=O)C[C@H]1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of methyl (1R,2R,4S)-4-hydroxy-2-methoxycyclohexanecarboxylate (racemic) (1.50 g, 7.97 mmol) in dichloromethane (40 mL) was treated with methanesulfonyl chloride (1.23 mL, 15.9 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h and partitioned between ethyl acetate and water. The organic phase was concentrated and purified on silica gel (eluting with 50% ethyl acetate in hexanes) to give the desired product (2.12 g, 91%). 1H NMR (400 MHz, CDCl3) δ 4.62 (1H, m), 3.71 (3H, s), 3.48 (1H, m), 3.33 (3H, s), 3.02 (3H, s), 2.64 (1H, m), 2.32 (1H, m), 2.19 (1H, m), 2.00 (1H, m), 1.60-1.42 (3H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH2:7][C:6]([CH3:14])=[CH:5][CH2:4][C:3]1=2.[OH2:16].[OH2:17].C[N+]([O-])(C)C>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH2:7][C:6]([CH3:14])([OH:16])[CH:5]([OH:17])[CH2:4][C:3]1=2
Reactant: O
Reactant: CC1=CCC2=C(C1)C(C)(C)CCC2(C)C
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: CC(C)(C)O
Product: CC1(C)CCC(C)(C)C2=C1CC(O)C(C)(O)C2
Reaction time: 48 h

Procedure:
253.3 g of hydrocarbon mixture containing about 60% of 2,2,5,5,8-pentamethyl-bicyclo[4.4.0]deca-1(6),8-diene are dissolved in 1050 ml of tert.butanol and treated with a solution of 91.65 g of trimethylamine N-oxide dihydrate in 375 ml of water. Thereto there is added a solution of 40 mg of osmium tetroxide in 75 ml of tert.butanol and the mixture is held for 48 hours at 95° C. with good stirring at reflux temperature. The solution is extracted with 2 l of dichloromethane, 1 l of water and 412.5 ml of 2N hydrochloric acid and ice. The organic phase is washed neutral twice with 1 l of water each time and the aqueous phases are extracted with dichloromethane. After drying over magnesium sulphate and concentration on a rotary evaporator, there are obtained 269 g of crude crystals. These are recrystallized from 150 ml of hexane and 80 ml of dichloromethane. There are obtained 167.0 g of crystalline 2,2,5,5,8-pentamethyl-bicyclo[4.4.0]dec-1(6)-ene-8,9-diol of melting point 98°-99.5° C.
Reaction SMILES: OC1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([Br:13])Br.[CH3:14]O>>[Br:13][C:11]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][N:3]=1
Reactant: BrCBr
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CO
Product: COC(=O)c1ccc(Br)nc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
6-Hydroxynicotinic acid (31 g) and methylene bromide (300 mL) were added at 18° C. to 98.9 g of phosphorous pentabromide while stirring with a mechanical stirrer under an argon atmosphere. The mixture was warmed to 70° C. over 2 hours, and further stirred for 16 hours. The mixture was cooled to 10° C. and 300 mL of methanol (CAUTION: EXOTHERMIC) was added. The cooling bath was removed and stirring was continued for 1/2 hour more. A solution of 76 g of K2CO3 in 610 mL of water was added and stirred for a few minutes. The layers were separated. The aqueous layer was extracted with methylene bromide. The combined organic phase was filtered through celite, washed with water and stripped. The residue was dissolved in 200 mL of ethanol on the steam bath. To this hot solution, 400 mL of water was added and the mixture was cooled in an ice bath. The precipitated solid was filtered, washed with 20% ethanol in water and air-dried to give 38.3 g of methyl 6-bromo-nicotinate as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.I[CH2:20][C@@H:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23]>O1CCCC1>[CH:11]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([CH2:20][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH3:23])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: CC[C@@H](CI)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H](C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC)c1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of (2R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (4.25 g, 23.1 mmol) in tetrahydrofuran (30 ml) was cooled to −78° C., then n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmol) was added and the mixture was stirred for 1 hour. A solution of ((R)-1-iodomethyl-propyl)-benzene (6.30 g, 24.2 mmol) in tetrahydrofuran (30 ml) was added dropwise over 30 min and the mixture was stirred overnight while being allowed to warm slowly from −70° C. to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a light yellow oil (4.69 g, 64%); MS (ISP): 317.0 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:5]CN.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH:20]=[CH:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25].[CH3:28][N:29](C)C=O>>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]#[C:22]/[CH:21]=[CH:20]/[CH2:19][N:29]([CH2:5][C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[CH3:28]
Reactant: Cc1cc(Br)cc(CCN)c1
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Br)cc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
N-(3-bromo-5-methylbenzyl)methylamine (2.68 g; 12.5 mmol) and sodium carbonate (1.89 g; 17.9 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred at room temperature, 1-bromo-6,6-dimethyl-2-hepten-4-yne (2.40 g; 11.9 mmol) in N,N-dimethylformamide (15 ml) was added dropwise. The mixture was stirred at room temperature for 1.5 hours, and reaction was stopped by pouring the mixture into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1), to thereby yield 2.24 g of the target compound (yield: 56.3%).
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[F:8][C:9]1[CH:10]=[C:11]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:12][C@H:13]([NH2:22])[C@@H:14]([OH:21])[C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19].[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([N:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])=[O:38])[CH:36]=1)[C:31](O)=[O:32].CCN(C(C)C)C(C)C>>[F:8][C:9]1[CH:10]=[C:11]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:12][C@H:13]([NH:22][C:31](=[O:32])[C:30]1[CH:29]=[C:28]([CH3:27])[CH:36]=[C:35]([C:37]([N:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])=[O:38])[CH:34]=1)[C@@H:14]([OH:21])[C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:2]
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCCC[C@@H](O)[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC[C@@H](O)[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cc(C)cc(C(=O)N(CCC)CCC)c1

Procedure:
The trifluoroacetate salt of (1S,2R,3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxyheptylamine (0.1 mmol) was reacted with 3-methyl-5-[(dipropylamino)carbonyl]benzoic acid as described in method A (addition of an extra equivalent of DIEA to neutralize the amine salt) to give N1-[(1S,2R,3R)-1-(3,5-Difluorobenzyl)-2,3-dihydroxy-octyl]-5-methyl-N3,N3-dipropyl-isophthalamide. MS (ESI+) for C29H40F2N2O4 m/z 519 (M+H)+.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=4[O:36][C:37]([F:40])([F:39])[F:38])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH:50]1([C:53](Cl)=[O:54])[CH2:52][CH2:51]1>C1COCC1>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[C:33]([NH:35][C:53]([CH:50]5[CH2:52][CH2:51]5)=[O:54])[CH:32]=[CH:31][C:30]=4[O:36][C:37]([F:39])([F:40])[F:38])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(N)ccc4OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)C5CC5)ccc4OC(F)(F)F)cc3)cc2)CC1
Yield: 32.2 %

Procedure:
A stirred solution of 5′-amino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid {4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenyl}-amide (50 mg) in dry THF (1 ml) was treated with N,N-diisopropylethylamine (60 μl) followed by cyclopropane carbonyl chloride (18 mg). After 16 h the mixture was evaporated and the residue purified by chromatography. Gradient elution with 0%-30% 20DCM:8EtOH:1NH3 in DCM over 35 mins gave the title compound as an off-white solid (18 mg).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[CH3:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[N:11]([C:29](=[O:30])[CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccc(C#N)cc2N1C(=O)CS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (106 mg, 335 μmol) in pyridine (3.35 ml) was added 2-(methylsulfonyl)acetic acid (50.9 mg, 369 μmol) followed by phosphoryl chloride (61.3 μl, 670 μmol), dropwise. The reaction was stirred at 0° C. for 30 min, then quenched by the addition of H2O and extracted with EtOAc. The combined organic layers were washed with 1 N aq. citric acid, H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (137 mg, 94%) as a white solid. MS m/z 459 (MNa)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.N12CCN(CC1)CC2.[C:20](#[N:23])[CH:21]=[CH2:22]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:22][C:21]([C:20]#[N:23])=[CH:4]2
Reactant: COc1ccc(O)c(C=O)c1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C=C(C#N)CO2

Procedure:
A solution of 0.61 g (4 mmol) of 2-hydroxy-5-methoxybenzaldehyde and 0.112 g (1 mmol) of 1,4-diazabicyclo[2.2.2]octane in 18 ml of acrylonitrile is heated at reflux for 24 hours under argon. After cooling, the medium is diluted with chloroform and then washed with a saturated solution of sodium hydrogen carbonate. The organic phase is then acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with chloroform. The organic phases, dried over magnesium sulphate and then filtered, are concentrated under reduced pressure. The title nitrile is obtained pure in the form of a yellow solid after passage over a silica column (eluant: AcOEt/PE: 25/75).