Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C([O-])(O)=O.[Na+].[C:36]([C:39]1[C:40]2[N:41]([N:46]=[N:47][N:48]=2)[N:42]=[C:43]([SH:45])[CH:44]=1)([OH:38])=[O:37].Cl>O>[C:36]([C:39]1[C:40]2[N:41]([N:46]=[N:47][N:48]=2)[N:42]=[C:43]([S:45][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:44]=1)([OH:38])=[O:37]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: O=C(O)c1cc(S)nn2nnnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)c4nnnn4n3)CS[C@H]12)c1csc(N)n1
Temperature: 50 °C

Procedure:
To a stirred solution of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) (0.456 g, 0.001 mole) and NaHCO3 (0.143 g, 0.0017 mole) in water (10 ml), 8-carboxy-6-mercapto-tetrazolo[1,5-b]pyridazine (0.138 g, 0.0007 mole) was added. A slow stream of nitrogen was passed through the solution, and the mixture was heated at 50° C. for 12 hours, while keeping the pH at 6.8. After cooling, the solution was acidified with 10% HCl, the precipitate collected by filtration, washed with water and then with ethanol. There was thus obtained 0.245 g of the title compound which was shown by N.M.R., T.L.C. and I.R. to be identical to the product described in Example 4, apart a minor contaminant of the anti-isomer.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])C(=O)[O-])(C)C.Cl>CO.O1CCOCC1>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:30])[F:31])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reaction time: 12 h
Yield: 109.2 %

Procedure:
To a solution of 1,1-dimethylethyl((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate (3.2 g, 7.1 mmol) in MeOH (35 mL) at RT was added 4M HCl in dioxane (18 mL). After 12 h, the solution was concentrated affording the title compound (2.7 g, quant.) as the HCl salt: LCMS (ES) m/z 349 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClCCl.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3[nH]c(CCCNC(=O)OC(C)(C)C)cc3c2)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(NC(=O)c2ccc3[nH]c(CCCN)cc3c2)cc1OC
Reaction time: 2 h

Procedure:
A 250 round bottom flask was charged with tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propylcarbamate (3.0 g, 6.62 mmol), dichloromethane (33 mL), and 1M hydrochloric acid in diethyl ether (33 mL) and the resulting mixture stirred for 2 h. The resulting mixture was then concentrated in vacuo, the residue triturated with diethyl ether, and placed under high vacuum to yield 2-(3-amino-propyl)-1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl)-amide. MS (ES+) 354 (M+1); HPLC: Kromasil C18 column (50×2 mm; 3.5μ), gradient 10-90% (MeCN+0.16% TFA) in (water+0.2% TFA) over 4 min, tR=2.46 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12](F)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[NH2:8])[CH:2]([CH3:4])[CH3:3].[CH3:22][OH:23]>C[O-].[Na+]>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12]([O:23][CH3:22])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[NH2:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CO
Reactant: CC(C)Cc1cc(N)ccc1C(F)(C(F)(F)F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Product: COC(c1ccc(N)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 79.6 %

Procedure:
3-Isobutyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (1.6 g, 5 mmol) was dissolved in a 28% by weight methanol solution (9.6 g) of sodium methoxide and stirred under heating for 3 hours. After cooling, the reaction solution was poured into ice water, followed by extracting with ethyl acetate and washing with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=5:1) to obtain 1.31 g of the desired compound.
Reaction SMILES: [C:1]1([Li])C=CC=CC=1.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=O)[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[CH2:1])[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Reactant: [Li]c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=C(CCCCC(C)(C)C(=O)OCC)CCCCC(C)(C)C(=O)OCC
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
Under nitrogen atmosphere, a solution of phenyllithium (in diethyl ether: cyclohexane=30:70, 7.06 mL, 1.8 M, 12.7 mmol) was added dropwise over 10 min to a solution of methyltriphenylphosphonium iodide (5.52 g, 13.3 mmol) in anhydrous THF (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, before 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (4.5 g, 12.2 mmol) was added and the reaction mixture was stirred for 5 h at 50° C. The resulting light-orange mixture was quenched by adding methanol (0.3 mL), and most of the solvent was removed on a rotary evaporator. The residue was purified by chromatography on silica (hexanes:ethyl acetate=95:5) to furnish the product (2.1 g, 47%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.67 (s, 2H), 4.10 (q, 4H, J=7.3 Hz), 1.97 (t, 4H, J=7.6 Hz), 1.6-1.3 (m, 8H), 1.30-1.15 (m, 10H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 149.6, 108.6, 60.1, 42.1, 40.6, 35.8, 28.2, 25.1, 24.7, 14.2. HRMS (LSIMS, nba): Calcd. for C22H41O4 (MH+): 369.3004. found 369.3009.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][N:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=[N:36]3)=[O:21])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)O)(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (91.5 mg) and 1-hydroxybenzotriazole (45.9 mg) were dissolved in N,N-dimethylformamide (2.0 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95.9 mg) was added and the mixture was allowed to warm to room temperature and was stirred for 15 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluant:ethyl acetate) to give (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (92.0 mg).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[C:11](Cl)[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=[C:17]([C:31]#[C:32][CH2:33][O:34][CH3:35])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].[ClH:39]>C(O)C>[Cl:39][C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=[C:17]([C:31]#[C:32][CH2:33][O:34][CH3:35])[CH:16]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:36]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)c(Cl)c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(Cl)c2)c1
Reaction time: 1 h

Procedure:
{5-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δH(400 MHz; CDCl3) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s, 3H), 3.56 (d, 2H), 3.78 (t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89 (s, 2H), 5.91-5.94 (m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03 (m, 1H), 7.40 (dd, 1H), 7.58 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[CH2:31]([Mg]Br)[CH3:32]>O1CCOCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1)[CH3:32]
Reactant: CC[Mg]Br
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CCCn1c(CC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 50 °C
Yield: 9.7 %

Procedure:
To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.239 mmol) in dioxane (5 ml) under argon was added ethyl magnesium bromide (0.05 g, 1.146 mmol, 1M solution) and 1M zinc chloride (0.031 g, 2.39 mmol, 1M). To this solution Pd(PPh3)4 (0.026 g, 0.0239 mmol) was added. The reaction mixture was heated at 50° C. for overnight. The reaction mixture was filtered through celite pad and the solvents were removed under reduced pressure. The residue was purified by column chromatography to obtain 2-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.01 g, 10%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH:1]1([C:4]2[C:8]([CH:9]([OH:10])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:7][N:6]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)C[Mg]Br
Reactant: COc1ccc(-n2cc(C=O)c(C3CC3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C(O)CC(C)C)c(C3CC3)n2)cc1
Yield: 82 %

Procedure:
3-Cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.8 g) synthesized above was dissolved in tetrahydrofuran (10 mL), isobutylmagnesium bromide (1M tetrahydrofuran solution, 12 mL) was added dropwise at 0° C. In the same manner as in Example 1(6), the title object compound (1.8 g, 82%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26]CC>>[CH:2]1([CH2:1][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[C:12]3[C:13]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=4[NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:26][CH2:3]1
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Reactant: CCCI
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OCC2CC2)c1

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting (bromomethyl)cyclopropane for 1-iodopropane while making non-critical variations the title compound was obtained as 74 mg (14%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1 H), 7.29-7.21 (m, 2 H), 7.12 (d, J=8.0 Hz, 1 H), 7.07-7.03 (m, 1 H), 6.98-6.94 (m, 1 H), 6.92 (d, J=8.2 Hz, 1 H), 6.86 (d, J=7.1 Hz, 1 H), 3.70 (d, J=6.3 Hz, 2 H), 3.01-2.95 (m, 2 H), 2.85-2.73 (m, 4 H), 2.37-2.31 (m, 2 H), 0.95-0.93 (m, 1 H), 0.30-0.25 (m, 2 H), 0.00-(−0.03) (m, 2 H); HRMS (FAB) calcd for C22H24N2O+H1: 333.1967 found 333.1955.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([F:23])=[C:8]2[C:3]=1[C:4](=[O:30])[C:5](C(O)=O)=[CH:6][N:7]2[CH:24]1[CH2:26][CH2:25]1.[C-]#N.[Na+]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([F:23])=[C:8]2[C:3]=1[C:4](=[O:30])[CH:5]=[CH:6][N:7]2[CH:24]1[CH2:25][CH2:26]1
Reactant: Nc1c(F)c(NCCNc2ccccn2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c(F)c2c1c(=O)ccn2C1CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 8 (100 mg, 0.24 mmol) and NaCN (117 mg, 2.4 mmol) in DMSO (2 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was purified by column chromatography (CH2Cl2: EtOAc 10:1) to yield 9 (71 mg, 80%) as a yellow solid.
Reaction SMILES: [CH:1]1(P)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:8]([Cl:13])(Cl)(Cl)(Cl)[Cl:9]>C1(C)C=CC=CC=1>[CH:1]1([P:8]([Cl:13])[Cl:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: PC1CCCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClP(Cl)C1CCCCC1

Procedure:
319 g (1.05 mol) of a 38 wgt % monocyclohexylphosphine solution in toluene was added dropwise at 25° C. to a suspension of 436 g PCl5 (2.1 mol) in 1 liter toluene. After the strongly exothermal reaction was complete, the reaction mixture was filtered using a reverse frit. 5 g orange colored solid matter remained behind. The clear solution (31P-NMR; δ P: 195 ppm, C6H11PCl2, 95 mol %) was distilled under vacuum.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([C:2]1([CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:12][CH2:11][CH2:10][O:1]1)[CH3:9]
Reactant: CCC(=O)CC(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1(CC(=O)OC)OCCO1
Temperature: 120 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a solution of methyl 3-oxopentanoate (3 g, 23.1 mmol) in toluene (30 mL) was added ethane-1,2-diol (3 mL, 70.2 mmol) and p-toluenesulfonic acid (500 mg, 2.91 mmol), the resulting mixture was stirred at 120° C. overnight. Then the mixture was concentrated and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate; then it was filtered and concentrated to give methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1.7 g, 42.5%) as yellow oil which was used without purification. Product tlc [petroleum ether/ethyl acetate (15:1) developed with iodine, Rf 0.6]
Reaction SMILES: [C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[OH-].[Na+]>C(OCC)C>[C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNCC
Reactant: ClCCC=C(c1ccccc1)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCN(CC)CCC=C(c1ccccc1)C1Cc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of 29.5 g. of 1-phenyl-1-(2-indanyl)-4-chloro-1-butene in 125 cc. of 95 percent (v/v) ethanolbenzene (commercial 2B ethanol) was added 100 cc. of diethylamine in one portion. The reaction mixture was shaken and heated in a sealed bomb to about 100° C for 16 hours. The reaction mixture was cooled to about 25° C. and the solvent was removed under reduced pressure to afford the product as an oily residue. The oil was dissolved in 400 cc. of diethyl ether and shaken with 5N sodium hydroxide and washed with water. The ethereal solution was dried and the solvent was removed under reduced pressure, affording 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene.
Reaction SMILES: Cl.N1([C:7]([CH:9]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10]2)=[O:8])CCCC1.P(Cl)(Cl)(Cl)=O.[CH3:23][C:24]1[N:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[CH:26][CH:25]=1>ClC(Cl)C>[CH3:23][C:24]1[N:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[C:26]([C:7]([CH:9]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10]2)=[O:8])[CH:25]=1
Reactant: Cc1ccc2ccccn12
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)C2CCc3nc[nH]c3C2)c2ccccn12
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 10 ml of dichloroethane were added 1.08 g of 5-pyrrolidinocarbonyl-4,5,6,7-tetrahydrobenzimidazole hydrochloride and 1.18 ml of phosphorus oxychloride, and the mixture was stirred at 80° C. for 1 hour. At the same temperature 0.69 g of 3-methylindolizine in 2 ml of dichloroethane was added dropwise thereto during 15 minutes. The mixture was refluxed while stirring for 3 hours after that the mixture was poured into 20 ml of ice-water, and then the mixture was stirred at room temperature for 30 minutes. After liquid-liquid separation, the aqueous layer was washed with 10 ml of dichloromethane. Further, the aqueous layer was adjusted to a pH of about 9 with an aqueous 20% sodium hydroxide solution and then extracted with 20 ml of chloroform-methanol (4:1) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed off under reduced pressure. The residue was washed with 20 ml of dichloromethane-ethylacetate (3:1) to obtain 1.00 g of 5-[(3-methylindolizin-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([C:26]([CH:28]=[CH2:29])=[O:27])[CH3:25].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:25]=[CH:24]/[C:26](=[O:27])[CH2:28][CH3:29])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)CC
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (160 mg, 0.36 mmol), ethylvinyl ketone (50 mg, 0.43 mmol) and Pd(OAc)2 (8 mg) in MeCN (2 mL) is added triethylamine (0.5 mL, 3.6 mmol) and the mixture is heated at 100° C. in a pressure vessel for 4 h. The mixture is filtered and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([NH:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986) (197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated with excess triethylamine at 0° C. followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0-10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]([CH2:29][CH2:30][C:31](Cl)=[O:32])([O:27][CH3:28])=[O:26].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31](=[O:32])[CH2:30][CH2:29][C:25]([O:27][CH3:28])=[O:26])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CCC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 24 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 2.1 eq of 3-carbomethoxypropionyl chloride in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica gel, 1:4 ethyl acetate:methylene chloride). The resulting product is slurried in ethyl acetate and filtered to give pure 4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoic acid, methyl ester (24%); mp 157.5°-158° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[OH:6])=[N+:2]=[N-:3].[C:14](OC=C)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@H:5]([O:6][C:14](=[O:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)=[N+:2]=[N-:3]
Reactant: Cc1cccc(C(O)CN=[N+]=[N-])n1
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](CN=[N+]=[N-])c1cccc(C)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 41.4 %

Procedure:
Dissolved 2-Azido-1-(6-methyl-pyridin-2-yl)-ethanol (4.300 g, 24.130 mmol) into 200 mL of toluene. To this was added vinyl acetate (9.22 mL, 100.00 mmol) and Lipase PS-C II (4.00 g). The mixture stirred for 4.5 h at RT and was monitored by 1H NMR. The reaction mixture was filtered through a bed of celite and rinsed with 100 mL of toluene. The filtrate was concentrated in vacuo. Dissolved residue into CH2Cl2, applied to a SiO2 Column and purified (5–30% EtOAc/hexanes) to give 2.20g of acetic acid (R)-2-azido-1-(6-methyl-pyridin-2-yl)-ethyl ester and 2.11 of (S)-2-azido-1-(6-methyl-pyridin-2-yl)-ethanol, ee % >99.