Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>CS(C)=O.O>[CH3:18][O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: COS(=O)(=O)OC
Reactant: OCCCCCCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCCCCCCCCCO
Temperature: 40 °C
Yield: 21.9 %

Procedure:
a 500-mL, one-necked, round-bottom flask equipped with a magnetic stirrer and stir bar was charged with 1,9-nonanediol (10.00 g, 62.3 mmol) in dimethyl sulfoxide (100 mL) and H2O (100 mL). To this was added slowly a solution of sodium hydroxide (5.0 g, 125.0 mmol) in H2O (10 mL) at room temperature. During addition of sodium hydroxide the reaction mixture generated heat and the temperature rose to ˜40° C. The mixture was stirred for one hour, and then dimethyl sulfate (16.52 g, 131 mmol) was added in four portions while maintaining the temperature of the reaction mixture at ˜40° C. The reaction mixture was stirred at room temperature overnight. Progress of the reaction was monitored by TLC (Note 1). TLC monitoring indicated that the reaction was 25% conversion. At this stage additional dimethyl sulfate (24.78 g, 196.44 mmol) was added and the resulting mixture was stirred at room temperature for an additional 24 h. After completion of the reaction, sodium hydroxide (10% solution in water) was added to the reaction mixture to adjust the pH of the solution to 11-13. The mixture was stirred at room temperature for 2 h and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with H2O (200 mL), brine (150 mL), dried over anhydrous sodium sulfate (20 g), filtered and concentrated in vacuo to obtain a crude product (14 g). The crude product was purified by column chromatography using 250-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (10-50%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 9-methoxy-1-nonanol (lot D-1027-155, 2.38 g, 21.9%). Completion of the reaction was monitored by thin layer chromatography (TLC) using a thin layer silica gel plate; eluent: 60% ethyl acetate in hexanes.
Reaction SMILES: Br[CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4].[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>C(O)(=O)C>[C:23]([O:26][CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4])(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(OC(C)=O)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (323 mg) in acetic acid (3 ml) was added potassium acetate (345 mg) and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-acetoxypropyl)-3-isobutyrylindole-6-carboxylate (207 mg).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[CH2:24][Cl:25]>CCO>[ClH:25].[CH3:30][O:29][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[CH:28]=1)[CH2:24][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: COc1cc(CCl)cc(OC)c1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: COc1cc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc(OC)c1
Product: Cl
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,5-dimethoxybenzyl chloride (0.293 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 189 mg of the product 206. 1H NMR (DMSO-d6) δ 11.37 (s, 2 H), 7.85-7.45 (m, 4 H), 7.20-6.90 (m, 6 H), 6.90-6.60 (m, 4 H), 5.78 (s, 2 H), 4.70 (s, 2 H), 3.78 (s, 6 H); MS: m/z 405 (M++1).
Reaction SMILES: C(N(CC)CC)C.CN1CCN(C)C1=O.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1.Cl[CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[CH:35]([S:36]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:24][CH:25]=1)(=[O:38])=[O:37])=[CH2:34]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCCc1ccc(C2=NNC(=O)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: C=CS(=O)(=O)NCCCc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
7.50 g of triethylamine was added to a 1,3-dimethyl-2-imidazolidinone suspension (75 ml) containing 7.51 g of 6-[4-(3-aminopropyl)phenyl]-4,5-dihydropyridazin-3(2H)-one, and the mixture was stirred at room temperature for 10 minutes. Then, a tetrahydrofuran solution (40 ml) containing 5.85 g of chloroethylsulfonyl chloride was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and precipitated crystal was collected by filtration and recrystallized from acetonitrile to obtain 5.39 g of 6-[4-(3-vinylsulfonylaminopropyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)#N.C(O)(=[O:21])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[O:21]
Reactant: CC(=O)O
Reactant: CCOC(=O)/C=C/c1n[nH]c2cc(C#N)ccc12
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)/C=C/c1n[nH]c2cc(C=O)ccc12
Temperature: 55 °C
Yield: 65 %

Procedure:
To a solution of (E)-ethyl 3-(6-cyano-1H-indazol-3-yl)acrylate (723 mg, 3 mmol) in pyridine (10 mL) was added acetic acid (3 mL), followed by a solution of NaH2PO2 (1.056 g, 12 mmol) in H2O (3 mL). The resulting mixture was stirred for 0.5 min at rt before Raney-Nickel 2400 (slurry in H2O, 0.6 mL) was added in one portion. The resulting mixture was heated at 55° C. (oil temp.) for 1 h before cooling to rt. H2O (30 mL) was added and the mixture was extracted with EtOAc (50 mL×2). Combined extracts were washed with H2O (20 mL), 2 M HCl (20 mL), H2O (20 mL×2), brine (15 mL) and dried (Na2SO4). Removal of solvent gave an orange red oil which solidified upon standing O/N under high vacuum. It was then triturated with H2O (30 mL) and suction filtered, rinsed with H2O, dried to give the title compound (476 mg, 65%) as an orange red solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.30 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.22 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS ESI 245.0 [M+H]+, calcd for [C13H12N2O3+H]+ 245.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.CC1C=CC(CCC(=O)C)=CC=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:11][CH2:10][CH:9]([OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)CCc1ccc(C)cc1
Product: Cc1ccc(CCCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3, replacing 2-(3-chlorophenyl)-2-hydroxy ethanamine by 2-(3-trifluoromethylphenyl)-2-hydroxyethanamine, and 4-methylphenylacetone by 4-(4-methylphenyl)butan-2-one. The chromatographed material was recrystallised from hexane to give the title compound mp 52°-55° as a 44:56 ratio of diastereoisomers.
Reaction SMILES: CN(C)C=O.[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1>O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To an N,N-dimethylformamide (20 mL) solution of thiophenol (1.02 g, 9.28 mmol) was added sodium hydride (446 mg, 9.28 mmol, 50% in oil), which was stirred for 15 minutes at room temperature. 2,5-Dibromopyridine (2.00 g, 8.44 mmol) was then added to this reaction mixture and stirred for 35 minutes at room temperature, and then for a further 45 minutes at 55° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate:=4:1) to obtain the title compound (2.24 g, quant.).
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>C(Cl)Cl.CO>[N:48]1([CH2:47][CH2:46][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[CH:38][CH:39]=2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: ClCCN1CCCCC1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: c1cc(-c2cnc(Nc3ccc(OCCN4CCCCC4)cc3)s2)cs1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 1-(2-chloroethyl)-piperidine hydrochloride. Title compound: ES-MS: 386.0 [M+H]+; single peak at tR=6.26 min (System 1); Rf=0.36 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2]1.[Br:11]Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:11][C:5]1[O:1][CH:2]=[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1
Reactant: CCOC(=O)c1ccoc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1coc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of ethyl 3-furoate (50.0 g, 360 mmol) in chloroform (380 mL) was added bromine (56.0 g, 360 mmol) in chloroform. The reaction mixture was allowed to stir at rt overnight and then poured into 10% aqueous Na2CO3. The mixture was extracted with DCM. The organic solutions were combined and washed with water until pH=7. The organic solution was concentrated and then distilled to give ethyl 5-bromo-3-furoate (42 g, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)(=O)C>ClCCCl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CNc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a solution of 4-nitrobenzaldehyde (3.02 g) and 2-aminopyridine (1.88 g) in 1,2-dichloroethane (70 ml) were added triacetoxy sodium boro hydride (5.93 g) and acetic acid (1.14 ml), and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours and concentrated. To the residue was added sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with brine, dried (anhydrous magnesium sulfate) and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1/1), and to the purified materials were added ethyl acetate/diethylether and 1N hydrochloric acid. The aqueous layer was extracted and washed with diethylether, and to the mixture was added sodium carbonate. The mixture was extracted with ethyl acetate, and the extract was dried (anhydrous magnesium sulfate), concentrated and recrystallized from ethyl acetate/hexane to give 2-[(4-nitrophenyl)methylamino]-pyridine (1.63 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (105 mg, 0.37 mmol) in methylene chloride (10 mL) and 1 drop of N,N-dimethylformamide was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.18 mL, 0.37 mmol). The reaction was stirred for 30 min at 0° C., at which time, 1,1,1,3,3,3-hexamethyldisilazane (0.25 mL, 1.17 mmol) was added to the reaction mixture. The reaction was then allowed to slowly warm to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then washed with a 5% aqueous sulfuric acid solution (2×10 mL). The combined aqueous layers were extracted with methylene chloride (3×10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (60 mg, 58%) as a white solid: [α]23589=−67.6° (c=0.106, chloroform); EI-HRMS m/e calcd for C14H17Cl2N1O1(M+) 285.0687, found 285.0685.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8].[N-:36]=[N+:37]=[N-:38].[Na+]>O.C(O)(C)C.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[NH:38][N:37]=[N:36][N:27]=3)[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(C#N)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(-c3nnn[nH]3)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 617 from (1R,3S,5R)-2-[2-(3-acetyl-6-cyano-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Example 616 (100.0 mg, 0.203 mmol), sodium azide (66.0 mg, 1.014 mmol) and zinc bromide (228.0 mg, 1.014 mmol) in water (2 mL) and isopropanol (1 mL). White solid. MS (LC/MS): 536.0 [M+H]+; tR (HPLC conditions k): 3.21 min.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]([N:41]1[C:45]([CH2:46][CH2:47][CH2:48]O)=[N:44][CH:43]=[N:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:48][CH2:47][CH2:46][C:45]1[N:41]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:42]=[CH:43][N:44]=1
Reactant: OCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -5 °C
Yield: 43.3 %

Procedure:
A solution of bromine (5.6 g) in dichloromethane (15 ml) was added dropwise to a stirred solution of triphenylphosphine (9.2 g) in dichloromethane (100 ml) cooled to -5° C. The mixture was stirred for a further ten minutes at 0° C., then treated portionwise with a solution of the above alcohol (6.9 g) and triethylamine (4.9 ml) in dichloromethane (30 ml) again maintaining the temperature below 0° C. The solution was stirred for a further ten minutes, filtered through a bed of silica, then chromatographed on silica, using dichloromethane-ether (25:1) as eluant, to give 1-bromo-3(1-trityl-1,2,4-triazol-5-yl)propane (3.5 g, m.p. 146-149° C.). NMR (CDCl3):δ 1.8(2H,m), 2.15(2H,t), 3.2(2H,t), 7.1-7.3(15H,m), 7.9(1H,s). 13C NMR was used to confirm the position of the trityl substituent.
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:15]1([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[CH2:17][CH2:16]1.C(=O)=O>C(OCC)C>[C:5]1([NH:11][C:12]2[N:14]=[C:20]([CH3:21])[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: N=C(N)Nc1ccccc1
Agent: O=C(O)O
Agent: O=C=O
Solvent: CCOCC
Product: Cc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
10 g (51 mmol) of phenylguanidine hydrogen carbonate and 9.7 g (77 mmol) of 1-cyclopropyl-1,3-butanedione are heated at 110° C. for 6 hours with stirring, the evolution of carbon dioxide which occurs subsiding as the reaction progresses. After the dark brown emulsion has been cooled to room temperature, 50 ml of diethyl ether are added and the mixture is washed twice with 20 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The dark brown oil which remains (=13.1 g) is purified by column chromatography over silica gel (diethyl ether/toluene: 5/3). After the eluant mixture has been evaporated off, the brown oil is made to crystallise and recrystallised from diethyl ether/petroleum ether at 30°-50° C. Light-brown crystals are obtained. Melting point: 67°-69° C.; yield: 8.55 g (38 mmol) (=74.5% of the theoretical yield).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][N:11]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:10]1=[O:26].Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].[Cl-].[O:41]=[C:42]1[NH:46][C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:44][N:43]1[CH:53]1[CH2:58][CH2:57][NH2+:56][CH2:55][CH2:54]1>O1CCCC1>[CH:23]1([CH2:22][N:11]2[CH2:12][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15][C@H:9]([NH:8][C:28]([N:56]3[CH2:57][CH2:58][CH:53]([N:43]4[CH:44]=[C:45]([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[NH:46][C:42]4=[O:41])[CH2:54][CH2:55]3)=[O:29])[C:10]2=[O:26])[CH2:25][CH2:24]1
Reactant: NC1CCC(c2ccccc2)CN(CC2CC2)C1=O
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CC[NH2+]CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
Triethylamine (0.070 mL, 0.51 mmol) was added to a solution of 3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one (131 mg, 0.51 mmol) and p-nitrophenyl chloroformate (102 mg, 0.51 mmol) in tetrahydrofuran (5 mL) at 0° C. After 0.5 h, triethylamine (0.18 mL, 1.28 mmol) and 4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidinium chloride (142 mg, 0.51 mmol) were added and the mixture was allowed to warm to ambient temperature. After 2 h, the mixture was concentrated. Purification by preparative reverse phase chromatography (DeltaPak C18, 15 □, 47 mm×300 mm, 65 mL/min: 5% CH3CN to 95% CH3CN over 60 min) afforded the racemic compound. The cis and trans enantiomers were both separated using a Chiralcel AD column eluting with 30% 2-propanol/hexanes→70% propanol/hexanes (0.1% diethylamine in hexanes) to give the title compound (50 mg). MS 528.3 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@H:13]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:27][CH3:26])=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH:9]([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)F)C(=O)NC1(C#N)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)F)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stream of nitrogen was passed through a suspension of the aryl bromide from Step 5 (65 mg), 4-(methylthio)phenylboronic acid (40 mg), 2 M Na2CO3 (0.22 mL) and DMF (1.0 mL) for 5 minutes. PdCl2dppf was then added and the reaction was warmed to 80° C. and stirred under nitrogen for 4 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and poured into a saturated solution of sodium bicarbonate. The ethyl acetate layer was separated and the aqueous further extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 50:50) to afford the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(N(CC)CC)C.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>O1CCCC1>[CH:14]([NH:17][C:18]([N:4]([CH3:3])[NH:5][CH3:6])=[O:19])([CH3:16])[CH3:15]
Reactant: CNNC
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNN(C)C(=O)NC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of N,N'-dimethylhydrazine dihydrochloride (1.33 g) and triethylamine (2.02 g) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added isopropyl isocyanate (851 mg). The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. The solvent was evaporated to give N-(isopropylcarbamoyl)-N,N'-dimethylhydrazine (771 mg) as an oil.