Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:9][CH2:10][C:11]3[N:12]([C:13]([CH3:16])=[N:14][N:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CN(C)C=O.CN(CN(C)C)C.C(Cl)(=O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:9][CH2:10][C:11]3[N:12]([C:13]([CH2:16][CH2:11][N:12]([CH3:13])[CH3:6])=[N:14][N:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1cccc(Cl)c1C(c1ccccc1Cl)=NC2
Agent: CN(C)CN(C)C
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CN(C)CCc1nnc2n1-c1cccc(Cl)c1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, a solution of 7-chloro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetramethyldiaminomethane and acetyl chloride (in 0.25 molar excess compared to the N,N,N',N'-tetramethyldiaminomethane) are reacted together to give 7-chloro-1-[2-(dimethylamino)ethyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]#[N:33])=[O:26]>CS(C)=O.CCOC(C)=O>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:4]12[CH2:10][CH:8]3[CH2:9][C:2]([NH:1][CH2:24][C:25]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]#[N:33])=[O:26])([CH2:3]1)[CH:6]([CH2:7]3)[CH2:5]2
Reactant: NC12CC3CC1CC(N1CCCC1=O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCC1=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred mixture of 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl)pyrrolidin-2-one prepared as in preparation 9 (0.25 g, 1.1 mmol) and K2CO3 (0.46 g, 3.3 mmol) in DMSO (5 mL) at an ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.16 g) in 40% yield. m/z (M+1) 357; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.4 Hz, 1H), 3.70-3.38 (m, 2H), 3.46 (s, 2H), 3.41 (t, J=7.0 Hz, 2H), 2.60 (dd, J=4.0, 10.2 Hz, 1H), 2.40-1.75 (m, 17H), 1.72-1.62 (m, 1H), 1.58-1.50 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][N:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.[OH-].[Na+]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:19][CH2:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: C#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(CNCCc2ccnc(Cl)c2)cc1
Temperature: 105 °C
Yield: 55.4 %

Procedure:
A mixture of 1.386 g of 2-chloro-4-ethynyl-pyridine (10.07 mmol), 2.65 ml of 4-tert-butyl-benzylamine (15.11 mmol), 0.58 ml of acetic acid (10.07 mmol) and 666 mg of sodium cyanoborohydride (95% purity, 10.07 mmol) in ethanol (12 ml) were heated to 105° C. in a sealed tube for 2 d. The reaction mixture was allowed to cool to RT, diluted with 3N NaOH solution and extracted with DCM. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. After column chromatography (heptane/EtOAc 100:0 to 0:100) 1.688 g (55%) of the title compound were isolated as a brown liquid. MS (ISP) 303.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(C=O)c(OC)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CO)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
To a stirred solution of 4-chloro-2,5-dimethoxybenzaldehyde (29.0 g, 145 mmol, 1 equiv) in absolute ethanol (550 mL) was added sodium borohydride (27.3 g, 723 mmol, 5 equiv). The reaction was allowed to stir at room temperature for 6 h and slowly quenched via dropwise addition of acetone. The reaction mixture was diluted with EtOAc, washed with brine (×2), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography on SiO2 (EtOAc/hexanes, 1:1) to give 28.0 g (96% yield) of 2 as a white solid: Mp 89-90° C.; Rf 0.53 (EtOAc/hexanes, 1:1); IR (neat) 3258, 2958, 2915, 1495, 1461, 1392, 1204, 1061, 719 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.90 (s, 1 H), 6.80 (s, 1 H), 4.55 (d, 2 H, J=4.2 Hz), 3.77 (s, 3H), 3.71 (s, 3 H), 3.10 (bs, 1 H); 13C NMR (75 MHz, CDCl3) δ 150.6, 148.7, 128.4, 120.8, 112.5, 112.4, 60.3, 56.5, 55.6; HRMS (ESI+) m/z calcd for C9H12O3Cl 203.0475, found 203.0465.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[S:21]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(CC(=O)OCc2ccccc2)c(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CC(=O)OCc2ccccc2)c(S(=O)(=O)N2CCOCC2)cc1OC
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 60.1 %

Procedure:
To a stirred mixture of (2-chlorosulfonyl-4,5-dimethoxy-phenyl)-acetic acid benzyl ester (15.0 g, 39.0 mmol) in anhydrous tetrahydrofuran (45 cm3) cooled to 0° C. in an ice bath under an atmosphere of dry nitrogen was added triethylamine (6.00 cm3, 43 mmol). The mixture was stirred 2 minutes and morpholine (3.75 cm3, 43 mmol) was added dropwise to form a solid mass. To efficiently stir the mixture additional anhydrous tetrahydrofuran (145 cm3) was added and the mixture was warmed to ambient temperature over 20 hours. Water was added to the mixture and extracted with ethyl acetate (2×100 cm3). The combined ethyl acetate extracts were dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford a crude tan solid. The crude solid was recrystallized from toluene (150 cm3) to afford the title compound as tan crystals (10.2 g, 60.2%) with a positive ion ESI (M+H)+436.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=1)=O>C(O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:17](=[O:16])[CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C(=O)c1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluorophenylacetonitrile (11.13 g, 82 mmol) was dissolved in absolute ethanol (100 ml) and sodium ethoxide (21wt % in EtOH) (46 ml, 123 mmol) was added in one portion. The resulting brown solution was stirred for 10 min. at room temperature. A solution of 2-chloropyridine-4-carboxylic acid methyl ester (14.1 g, 82 mmol) in absolute ethanol (100 ml) was then added to the reaction over 3-5 min. The reaction mixture was then refluxed for 2 h during which time the color turned to dark brown. The reaction mixture was concentrated in vacuo and water (100 ml) was added to the resulting residue. The pH of the reaction mixture was adjusted to 3 using 10% hydrochloric acid. The product was extracted with ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-(2-chloropyridin-4-yl)-2-cyano-2-(4-fluorophenyl)ethanone as a dark brown solid which was used without further purification (22.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([N:24]([CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH2:50][NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49]>>[CH3:29][O:28][CH2:27][CH2:26][CH2:25][N:24]([C:4]1[N:5]=[C:6]([N:8]([CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:19][CH2:20][CH2:21][O:22][CH3:23])[N:7]=[C:2]([NH:40][CH2:41][CH2:42][CH2:43][CH:44]([CH2:50][NH:51][C:2]2[N:7]=[C:6]([N:8]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]3)[N:5]=[C:4]([N:24]([CH:30]3[CH2:31][C:32]([CH3:39])([CH3:38])[NH:33][C:34]([CH3:36])([CH3:37])[CH2:35]3)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=2)[CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:2]2[N:3]=[C:4]([N:24]([CH:30]3[CH2:31][C:32]([CH3:38])([CH3:39])[NH:33][C:34]([CH3:37])([CH3:36])[CH2:35]3)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:5]=[C:6]([N:8]([CH:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]3)[CH2:19][CH2:20][CH2:21][O:22][CH3:23])[N:7]=2)[N:3]=1)[CH:30]1[CH2:31][C:32]([CH3:39])([CH3:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH2:35]1
Reactant: NCCCCC(CN)CCCN
Reactant: COCCCN(c1nc(Cl)nc(N(CCCOC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Product: COCCCN(c1nc(NCCCCC(CCCNc2nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)n2)CNc2nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)n2)nc(N(CCCOC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Following the procedure described in Example 1, 2-chloro-4,6-bis[N-(3-methoxypropyl)-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,3,5-triazine [prepared as described in Preparation 6(b)] and 1,8-diamino-4-aminomethyloctane were reacted together and the reaction mixture treated to yield a residue, which was purified by column chromatography through silica gel, eluted with 4:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the desired Compound No. 32, in the form of crystals melting at 96°-99° C.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.O[CH:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:14]1[CH2:16][CH:15]1[C:17]#[N:18].[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[C:37]([CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[NH:35][CH:34]=[CH:33]2>ClCCCl>[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[C:37]([CH2:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH:38]=1)[NH:35][CH:34]=[C:33]2[CH:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:14]1[CH2:16][CH:15]1[C:17]#[N:18]
Reactant: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3C#N)c[nH]c12

Procedure:
33.0 mg (0.15 mmol) of indium(III) chloride and 0.02 ml (0.22 mmol) of trifluoroacetic acid were added to 30.0 mg (0.12 mmol) of the compound from Example 160A and 41.4 mg (0.15 mmol) of the compound from Example 87A with a purity of 82% under argon in 1 ml of 1,2-dichloroethane, and the mixture was heated under reflux for three days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 12.6 mg (23% of theory) of diastereomer 1 and 13.2 mg (24% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)[N:3]=1.[C:24]([O-:27])(O)=[O:25].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:27][C:24](=[O:25])[NH:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:18]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](NC(=O)OCc4ccccc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (125 mg, 0.324 mmol) in THF (4 mL) and saturated NaHCO3 (2 mL) was added phenylmethyl chloridocarbonate (0.055 mL, 0.389 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL), then extracted with EtOAc (3×10 mL). The organic was combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated to afford the crude title compound (155 mg) as a yellow oil. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=1[Cl:30]>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[C:21]=3[Cl:30])[C:10](=[O:11])[C:5]2=[N:4][N:3]=1
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Reactant: O=C1NCCn2c(Br)nnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2nnc(Br)n2CCN1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
To a slurry of 3-bromo-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one (294 mg, 1.4 mmol) and cesium carbonate (1.32 g, 4.1 mmol) in DMF (10 mL) was added 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene (446 mg, 1.6 mmol). After 5 h, the reaction mixture was poured into ice cold brine (200 mL). The resulting precipitate was filtered and washed successively with water and ether to provide the product as a white solid (456 mg, 82%). MS (ESI): mass calcd. for C13H9BrClF3N4O, 408.0; m/z found, 409.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 4.85 (s, 2H), 4.36-4.24 (m, 2H), 3.99-3.83 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:4]4[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@@H](C)O[C@@H](C)C3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
Following the same procedure in Example 3, Step A, using (2R,6S)-2,6-dimethylmorpholine (34.6 mg, 0.30 mmol), diisopropylethylamine (69.7 μL, 51.7 mg, 0.40 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (65.9 mg, 0.20 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (91.3 mg, 0.24 mmol). The mixture was stirred overnight at room temperature, added H2O (50 mL), extracted with EtOAc (3×50 mL). The desired title compound was purified by MPLC (hex/EtOAc 1:1 as eluent on silica gel) to give 75.7 mg (89%) of a white solid. 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.52 Hz, 3 H), 1.04 (m, 3 H), 1.28 (m, 8 H), 1.66 (m, 2 H), 1.69 (s, 6 H), 1.71 (m, 1 H), 1.79 (m, 2 H), 2.04 (q, J=7.42 Hz, 2 H), 2.13 (m, 1 H), 2.63 (m, 1 H), 2.92 (m, 1 H), 3.58 (m, 3 H), 4.50 (d, J=7.62 Hz, 2H), 4.55 (m, 1 H), 7.65 (dd, J=8.69, 1.46 Hz, 1 H), 7.81 (d, J=0.78 Hz, 1 H), 8.01 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)+=426.2. Anal. Calcd for C26H39N3O2+1.60 TFA+0.30 H2O (613.46): C, 57.17; H, 6.77; N, 6.85. Found: C, 57.18; H, 6.69; N, 6.88.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(CO)ccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CCCOc1ccc(CO)cc1OC
Yield: 47.1 %

Procedure:
4-Hydroxy-3-methoxybenzyl alcohol (1 g, 6.49 mmol) is treated with 1.73 g (7.13 mmol) of ethyl 4-bromobutyrate, 2.69 g (19.46 mmol) of potassium carbonate and a catalytic amount (97.22 mg 0.65 mmol) of sodium iodide as described in Preparation 3 to give 821 mg of 4-[4-(hydroxymethyl)-2-methoxyphenoxy]butanoic acid, ethyl ester as a light brown oil (47%). The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3500, 1730, 1620, 1600 cm-1 ; MS (CI (low res)) m/e 269 (M+H), 251, 223, 195.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[S:17][CH:16]=[N:15][C:14]=2/[C:13](=C/C(OC)=O)/[CH2:12][CH2:11][C@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:32]=[O+][O-]>C(Cl)Cl>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[C@@H:10]1[CH2:11][CH2:12][C:13](=[O:32])[C:14]2[N:15]=[CH:16][S:17][C:18]=2[C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)/C=C1\CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2scnc21
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2scnc2C(=O)CC[C@H]1c1cccc(F)c1F
Yield: 58 %

Procedure:
A solution of (E)-methyl 2-((7S,8S)-8-(tert-butoxycarbonylamino)-7-(2,3-difluorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-4-ylidene)acetate (68 mg, 0.15 mmol) in methylene chloride (5 mL) was treated with ozone under −78° C. for 2 min. The reaction mixture was purged with nitrogen and quenched with dimethyl sulfide. The solvent was removed under vacuum and the product was purified by flash chromatography, eluting with ethyl acetate in hexane from 0 to 100% to afford the desired product (34.5 mg, 58%): 1H NMR (400 MHz, CHLOROFORM-d) δ 8.73 (s, 1H), 7.16-7.09 (m, 3H), 5.62-5.53 (m, 1H), 5.13-5.05 (m, 1H), 3.64-3.53 (m, 1H), 3.13-3.02 (m, 1H), 3.01-2.92 (m, 1H), 2.38-2.24 (m, 2H), 1.36-1.29 (m, 9H); 19F NMR (400 MHz, CHLOROFORM-d) δ −137.33, −141.96.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][CH3:25])(=[O:23])/[CH:21]=[CH:22]/[CH:2]=[CH:1]/[CH3:6]
Reactant: C=CC(=O)OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Product: C/C=C/C=C/C(=O)OC
Temperature: 120 °C
Yield: 4 %

Procedure:
Quantities of 1.1 grams palladium acetate, 5.25 grams triphenyl phosphine, 42 cc alkyl bromide, 45 cc methyl acrylate and 119 cc tributyl amine are introduced into a reactor chamber and heated to 120°C for 27 hours. The resulting reaction mass is extracted with ether followed by distillation yielding 2.9 grams (4% yield) of methyl sorbate and alkyl-tributyl ammonium bromide as the major product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[OH:34])[C:5]([NH:7][NH:8][S:9]([NH:12][C:13]([N:15]1[CH2:18][C@H:17]([NH:19]C(=O)OCC2C=CC=CC=2)[C:16]1=[O:30])=[O:14])(=[O:11])=[O:10])=[O:6].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].C1(SC)C=CC=CC=1>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:19][C@H:17]1[CH2:18][N:15]([C:13]([NH:12][S:9]([NH:8][NH:7][C:5](=[O:6])[C:4]2[CH:31]=[CH:32][C:33]([OH:34])=[C:2]([OH:1])[CH:3]=2)(=[O:10])=[O:11])=[O:14])[C:16]1=[O:30]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[1-[[[[2-(3,4-Dihydroxybenzoyl)hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (0.8 g) was added to a mixture of 3 ml of trifluoroacetic acid and 0.75 ml of thioanisole and the mixture was stirred overnight at room temperature. The trifluoroacetic acid was removed in vacuo and the residue triturated with ether to yield 0.5 g of (S)-3-amino-N-[[2-(3,4-dihydroxybenzoyl)hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate salt.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:29])=[C:19]([F:28])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:29][C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[O:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:19]=1[F:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2c(F)c(F)cc(-c3ccccc3)c2O1
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.40 mmol) in N,N-dimethylformamide (25 mL) was added sodium azide (0.781 g, 12.02 mmol) and the reaction mixture was heated to 70° C. and allowed to stir for 3 h. The reaction mixture was allowed to cool and the solvent was removed in vacuo to provide a crude solid. The residue was suspended in ethyl acetate (100 mL) and washed with water (50 mL) and aqueous sodium chloride (50 mL), was dried (sodium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.68 g (99%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide as a white solid. Rf=0.93 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) δH 7.65 (d, 2H); 7.41 (m, 3H); 7.31 (t, 1H); 5.15 (m, 1H); 3.64 (m, 2H); 3.46 (dd, 1H); 3.10 (dd, 1H).
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH3:13][C:14](=[O:17])[C:15]#[CH:16]>C1C=CC=CC=1>[C:14]([C:15]1[CH:16]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1)(=[O:17])[CH3:13]
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC(C)=O
Solvent: c1ccccc1
Product: CC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A solution of 19.0 g (0.119 mole) of 3-diazooxindole and 10 g (0.147 mole) of 3-butyn-2-one in 800 ml of benzene is refluxed overnight. The reaction mixture is cooled to room temperature and the product filtered off (23.1 g). Recrystallization from methanol/chloroform gives 18.0 g of product with melting point 296°-299° (d). Further recrystallization from glacial acetic acid gives 14.2 g of pure product melting at 306°-308° (d).