Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]([CH3:17])[CH2:15][OH:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26].O>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:14]([CH3:17])[CH2:15][O:16][C:25]1=[O:26])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1ccc(NC(C)CO)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(N2C(=O)OCC2C)c(Cl)c1
Temperature: 25 °C

Procedure:
0.50 g (1.94 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are placed in 30 ml THF together with 0.22 g (2.20 mmol) triethylamine and 1.10 ml (2.08 mmol) 20% phosgene solution in toluene is added with stirring at ambient temperature. The mixture is stirred for 1 hour at ambient temperature, then 1 ml of water is added and the mixture is stirred for another 10 minutes. The mixture is then evaporated down i. vac., combined with water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [OH:1][C:2]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CO>[OH:1][C:2]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCCN1CCc1ccccc1
Solvent: CO
Product: Oc1cccc2c1CCC1C2CCCN1CCc1ccccc1
Yield: 50 %

Procedure:
Cis-(+)-7-hydroxy-4-phenethyl-1,2,3,4,4a,5,6, 10b-octahydrobenzo[f]quinoline (hereinafter, “cis-(+)-25”) was prepared in 50% yield from 37 mg (0.12 mmole) of cis-(+)-24 by the method of forming trans-9 as described in Example 3. The melting point observed was 194° C. and [α]D (20° C.) was +6.05 (c 0.22, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)#[CH:14]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[C:13][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: C#Cc1cncc(OC)c1
Reactant: Fc1ccc(I)cc1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C(F)(F)F)c2)c1
Temperature: 70 °C
Yield: 99.2 %

Procedure:
Dissolve 1-fluoro-4-iodo-2-trifluoromethylbenzene (813 mg, 2.8 mmol) in triethylamine (6 mL). Add 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) followed by bis(triphenylphosphine)palladium (II) dichloride (0.100 g, 0.14 mmol) and copper (I) iodide (53 mg, 0.28 mmol). Heat at 70° C. for 16 h, concentrate, and purify using silica gel chromatography, eluting with 100:0 to 90:10 methylene chloride:ethyl acetate, to give the title compound as a pale yellow solid (820 mg, 99%).
Reaction SMILES: C(OC([NH:8][N:9]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@@H:29]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:30][C@H:31]([OH:50])[C@@H:32]([NH:40][C:41]([O:43][CH2:44][C:45]1[S:49][CH:48]=[N:47][CH:46]=1)=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[S:14][CH:15]=1)=O)(C)(C)C.[ClH:58].C(OCC)C>O1CCOCC1.CO>[ClH:58].[NH2:8][N:9]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@@H:29]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:30][C@H:31]([OH:50])[C@@H:32]([NH:40][C:41]([O:43][CH2:44][C:45]1[S:49][CH:48]=[N:47][CH:46]=1)=[O:42])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:27])[CH:23]([CH3:24])[CH3:25])=[O:20])[CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:17])[CH3:18])[S:14][CH:15]=1
Reactant: CC(C)c1nc(CN(NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CC(C)c1nc(CN(N)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 60 mg (0.073 mmol) of (2S,3S,5S)-5-(N-(N-((N-(tert-butyloxycarbonyl-amino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane was added 5 ml of 4M HCl in dioxane. The resulting solution was stirred at ambient temperature for 2 h. After concentration of the solution in vacuo, the residue was taken up in 0.5 ml of methanol, added to 20 ml of diethyl ether, and filtered to provide 40 mg (77%) of the desired compound (Rf 0.60, 10% methanol in chloroform). Mass spectrum: (M+H)+ =722.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[CH:15](O)=O>>[CH2:1]([N:5]1[C:10]2[N:11]=[CH:15][NH:12][C:9]=2[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: O=CO
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of 36.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) in 100 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 42.9 g (not dried). (XI). The amide (XI) was refluxed in 100 ml of 2 N NaOH for 2 hours and then neutralized with 5 N HCl. The crystals were filtered off and washed with ethanol. Yield 28.4 g (74%) (XII), NMR. ##STR8##
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:35])=[C:25]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])[N:26]=2)=[CH:18][CH:17]=1>>[CH3:35][C:24]1[O:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[CH:17][CH:18]=2)=[N:26][C:25]=1[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH3:34]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1oc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-triflouromethoxy phenyl boronic acid (295 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 63 mg (51%). MS (m/e) 431.2 (M+1)
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH3:11])[N:7]=[C:6]([NH:16][C@H:17]([CH2:19][CH3:20])[CH3:18])[CH:5]=1.[OH-].[K+:23].Cl>O>[K+:23].[C@@H:17]([NH:16][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH3:11])[N:7]=1)[C:3]([O-:21])=[O:2])([CH2:19][CH3:20])[CH3:18]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC[C@H](C)Nc1cc(C(=O)[O-])cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
Heat a mixture of (S)-(+)-2-sec-butylamino-6-(methanesulfonyl-methylamino)-isonicotinic acid methyl ester (12.66 g, 0.04014 mol) and potassium hydroxide (2.7 g, 0.04817 mol, 1.2 eq) until dissolved. Dilute with water (62 mL) and was heat to reflux for 3 h. Cool to room temperature and add 1 N HCl (8 mL). Concentrate and add dichloromethane (300 mL) and stir well. Filter and concentrate filtrate to give the title compound as a yellow solid (13.62 g, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][O:22]CC3C=CC=CC=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:31]
Reactant: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCO
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of 9-(2-benzyloxy-ethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (36) (600 mg, 1.4 mmol) in methanol (40 mL) was added a slurry of Pd/C (100 mg) in methanol (5 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo to afford 460 mg (80%) of 6-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (37) as a yellow oil which was used in the next step without purification. The structure was confirmed by 1H NMR (300 MHz, MeOD-d3) δH 1.18 (3H, t, J=9 Hz, N(CH2CH3)2), 1.35 (3H, t, J=9 Hz, N(CH2CH3)2), 1.80-2.20 (4H, m, 2- and 3-CH2), 2.69-3.88 (2H, m, 1-CH2), 3.40-3.86 (6H, m, N(CH2CH3)2 and NCH2CH2OH), 4.03-4.22 (3H, m, NCH2CH2OH and 4-CH), 6.75-6.95 (2H, m, NCCHCHCFCH), and 7.05-7.15 (1H, m, NCCHCHCFCH.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15]([OH:17])=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].C(N(CCCC)CCCC)CCC.ClC(OCC(C)C)=O.[NH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C.CCOC(C)=O>[C:47]([O:46][C:45]([NH:44][CH2:43][CH2:42][NH:41][C:15]([C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])[CH:13]=2)=[O:17])=[O:51])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(CC)c1ccc2cc(C(=O)O)c(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CCN(CC)c1ccc2cc(C(=O)NCCNC(=O)OC(C)(C)C)c(=O)oc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
--A solution of 7-diethylaminocoumarin-3-carboxylic acid 2 (1.15 g, 5 mmol) and tri-n-butylamine (1.38 g, 7.5 mmol) in dry DMF (50 ml) was cooled in an ice bath and treated with isobutyl chloroformate (0.715 g, 5.2 mmol). The solution was stirred in the ice bath for 0.5 h, then a solution of the amine 3 (0.8 g, 5 mmol) in dry DMF (5 ml) was added. The mixture was allowed to warm to room temp. and kept for 3 h, then diluted with EtOAc and washed thoroughly with water, dilute aq. HCl, aq. NaHCO3 and water, dried and evaporated. The residue gave a yellow solid after trituration with a little ether. A portion (400 mg) was purified by flash chromatography to give the amide 4 as yellow prisms (0.345 g), m.p. 157-158° C. after crystallisation from EtOAc-light petroleum The remaining material crystallised without chromatography to give a further portion of the product (0.55 g, total yield 45%) (Found. C, 62.6;. H, 7.3; N, 10.4. C21H29N3O5 requires C, 62.5; H, 7.2; N, 10.4%); δH 8.95 (1 H, t, J 5.5, NH), 8.68 (1 H, s, 4-H), 7.42 (1 H, d, Jortho 8.8, 5-H) , 6.64 (1 H, dd, Jmeta 2.3, 6-H), 6.49 (1 H, d, 8-H), 5.08 (1 H, br S, NH), 3.23-3.64 (8 H, m, 4×CH2), 1.44 (9 H, S, CMe3) and 1.24 (6 H, t, J7, 2×Me).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([CH:13]=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][C@@H:9]1[CH2:12][C@H:11](/[CH:13]=[N:21]/[S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](C=O)C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a solution of cis-3-(tert-butyldimethylsilanyloxy)-cyclobutanecarbaldehyde (crude from step 3, 900 mg, 4.2 mmol) and 2-methylpropane-2-sulfinamide (509 mg, 4.2 mmol) in dry CH2Cl2 (10 mL) was added anhydrous CuSO4 (1.47 g, 9.24 mmol). The heterogeneous reaction mixture was stirred at room temperature overnight then filtered over Celite, rinsing with CH2Cl2. The filtrate was absorbed onto SiO2 and purified via chromatography with 0% to 20% EtOAc/hexanes to isolate 642 mg (48%) of 2-methyl-propane-2-sulfinic acid 1-[cis-3-(tert-butyldimethylsilanyloxy)-cyclobutyl]-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (d, J=5.3 Hz, 1H), 4.25 (quin, J=7.4 Hz, 1H), 2.73-2.88 (m, 1H), 2.46-2.59 (m, 2H), 2.06-2.18 (m, 2H), 1.19 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:19]=[CH2:18]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 2-chloro-5-nitrophenol (13.0 g, 75.1 mmol) in DMF (150 mL) was added K2CO3 (15.5 g, 113 mmol). The mixture was cooled to 0° C., and allyl bromide (9.60 mL, 113 mmol) was added dropwise. The reaction was then allowed to stir overnight at rt under nitrogen. The reaction was concentrated to remove DMF, then EtOAc was added to the residue. The mixture was washed with water and brine. The organic layer was dried (Na2SO4), and concentrated in vacuo to afford the highly yellow solid 2-(allyloxy)-1-chloro-4-nitrobenzene (11.5 g, 72% yield). LC-MS (M+H)+212.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.81-7.77 (2H, m), 7.52 (1H, d, J=8.8 Hz), 6.12-6.02 (1H, m), 5.54-5.37 (2H, m), 4.72-4.70 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:23]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>CO.[Pt]>[NH2:23][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:13]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Yield: 80 %

Procedure:
A suspension of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (3.89 g, 10 mmol) in methanol (80 ml) containing 10% platinum on activated carbon (50% wet) (389 mg) was hydrogenated at 1.8 atmospheres pressure until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in water (30 ml) and adjusted to pH10 with a saturated solution of sodium hydrogen carbonate. The mixture was diluted with ethyl acetate/ether (1/1) and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate/ether and the organic layers were combined. The organic layers were washed with water, brine, dried (MgSO4), filtered and evaporated. The resulting solid was triturated in a mixture of ether/petroleum ether, filtered, washed with petroleum ether and dried under vacuum at 60° C. to give ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (2.58 g, 80%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(NS(=O)(=O)C3CC3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (300 mg, 0.934 mmol) and DMAP (115 mg, 0.934 mmol) were dissolved in 10 mL of DCM. Cyclopropanesulfonyl chloride (170 mg, 1.21 mmol) was added and the solution was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.143 mL, 1.86 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 390 mg (77%). 1H NMR (400 MHz, METHANOL-D4) δ 0.91-0.97 (m, 2 H), 1.02-1.08 (m, 2 H), 1.48-1.60 (m, 2 H), 1.65 (s, 9 H), 1.67-1.75 (m, 3 H), 1.75-1.82 (m, 1 H), 2.00-2.10 (m, 2 H), 2.18-2.28 (m, 1 H), 2.53-2.61 (m, 1 H), 4.50 (d, J=7.42 Hz, 2 H), 7.42 (dd, J=8.98, 2.15 Hz, 1 H), 7.74 (d, J=1.56 Hz, 1 H), 7.85 (d, J=8.79 Hz, 1 H); MS (ESI) (M+H)+ 426.0; Anal. Calcd (%) for C21H29N3O2SF2+1.0 TFA; C, 51.20; H, 5.60; N, 7.79. Found: C, 51.38; H, 5.66; N, 7.56.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[C:4](OC)=[C:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26]>C(O)C>[OH:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]2[C:5]([N:26]=[C:21]3[C:20](=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22]3)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: CCOC(=O)C1=C(OC)C(=O)c2ccccc2C1=O
Reactant: Nc1ccccc1N
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2c2nc3ccccc3nc12
Yield: 92.4 %

Procedure:
A mixture of 2.63 g of ethyl 1,4-dihydro-1,4-dioxo-3-methoxy-2-naphthoate and 1.3 g of o-phenylenediamine in 50 ml of ethanol was heated at reflux for an hour. After cooling, the precipitated solid was collected by filtration and recrystallized from ethanol to give 2.972 g (93.5% yield) of ethyl 5-hydroxybenzo[a]phenazine-6-carboxylate as yellow needles, m.p. 126°-127° C., Anal. CAlcd. (%) for C19H14N2O3 : C, 71.69; H, 4.43; N, 8.80; Found: C, 71.81; H, 4.21; N, 8.90
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][NH2:13])(=O)=O)=CC=1.N1C=CC=CC=1.Cl[P:22]1(=[O:27])[O:26][CH2:25][CH2:24][O:23]1>C(#N)C>[NH2:13][CH2:12][CH2:11][O:10][P:22]1(=[O:27])[O:26][CH2:25][CH2:24][O:23]1
Reactant: O=P1(Cl)OCCO1
Reactant: Cc1ccc(S(=O)(=O)OCCN)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: NCCOP1(=O)OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethanolamine p-toluenesulphonate (10.0 g, 39.8 mmol was dissolved in dry acetonitrile (500 ml) at 60° C. The solution was cooled to 30° C. when pyridine (3.15 g, 39.8 mmol) was added. A solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (5.68 g, 39.8 mmol) in dry acetonitrile (5 ml) was then added over 10 minutes. The mixture was stirred at ambient temperature for 4 hours and then the acetonitrile evaporated in vacuo to give 2-(2-aminoethoxy)-2-oxo-1,3,2-dioxaphospholane as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[O:15])[C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:10](=[O:12])[CH:9]([NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Reactant: COc1cccc(C(NC(=O)Nc2ccccc2F)C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)C(NC(=O)Nc2ccccc2F)c2cccc(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 3-methoxy-[N′-(2-fluorophenyl)ureido]phenylacetic acid (296 mg, 0.93 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (240 mg, 0.93 mmol), EDC (hydrochloride) (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temp for 1.5 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 520 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-[N′-(2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a red-brown amorphous solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH3:20][S:17]([O:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])[CH2:13]1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCC(=O)NC(N)=O)C1

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (3.00 g) in a mixture of methanol (30 ml) and tetrahydrofuran (60 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 5 hours in the presence of 20% palladium hydroxide on carbon (1 g). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (20 ml) and water (20 ml) was dropwise added a solution of allyl chloroformate (0.82 ml) in tetrahydrofuran (2 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (15 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (1.11 g).
Reaction SMILES: [F-].[Cs+].[C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:10]=1[F:11])#[N:4].Cl[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1

Procedure:
Cesium fluoride and tetrakis(triphenylphosphine)-palladium were added to a 1,2-dimethoxyethane solution of (3-cyano-4-fluorophenyl)boronic acid and methyl 2-chloroisonicotinate, followed by reaction under heating to reflux to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.