Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([OH:38])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:41]([F:44])([F:43])[F:42].C([O-])([O-])=O.[Na+].[Na+].[C:51](OC=C)(=O)[CH3:52]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([O:38][CH:51]=[CH2:52])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:41]([F:44])([F:43])[F:42]
Reactant: C=COC(C)=O
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264, 100 mg, 0.158 mmol) in toluene (0.2 ml) was added Na2CO3 (25 mg, 0.235 mmol) and catalytic amount of [Ir(cod)Cl]2 (2 mg), followed by vinyl acetate (68 mg, 0.79 mmol). The reaction mixture was stirred at 100° C. for 16 h. The resulting mixture was filtered and the solid was washed with CH2Cl2. The CH2Cl2 layer was washed with 1 N NaOH, H2O and the organic portion dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column using 0 to 60% EtOAc in hexane to afford (R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide eluting out at 20% EtOAc in hexane as colorless oil (80 mg, 77%). LCMS: RT=2.237 min [M+H] 658.3 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 Ml/min, monitoring at 220 nm. NMR: 400 MHz 1H (CD3OD) ppm 3.87 (d, J=12.74 Hz, 1H), 4.05-4.15 (m, 1 H), 4.35 (dd, J=5.93, 1.98 Hz, 1H), 4.55 (dd, J=13.84, 1.98 Hz, 1H), 6.12-6.41 (m, 1H), 6.48 (dd, J=13.62, 6.15 Hz, 1H), 6.72 (d, J=7.03 Hz, 2H), 6.87-7.24 (m, 9 H), 7.37-7.51 (m, 1H), 7.88-8.04 (m, 2H).
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:17]=[CH:16][C:8](/[CH:9]=[CH:10]/[C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)cc1

Procedure:
A solution of 4 g. of sodium hydroxide in 30 ml. of water is added to a solution of 19.4 g. (0.1 mole) of ethyl trans-4-fluorocinnamate (Compound LXV) in 350 ml. of ethanol, and the reaction mixture is stirred at 70° C. for 18 hours. The solvent is evaporated at reduced pressure, and the residue is dissolved in water. The solution is washed once with methyl t-butyl ether and acidified with 6N. hydrochloric acid. The resulting precipitate is washed twice with water and dried to obtain the product (15.5 g. (93%)). An analytical sample was recrystallized from ethyl acetate, m.p. 204°-206° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1>C(O)C>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CCC2)ncn1

Procedure:
150 mg (0.5 mmol) of the compound from Example 23 and 63 mg (1 l mmol) of azetidine are suspended in 4 ml of ethanol and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 40 min. The solid is filtered off, washed twice with in each case 0.5 ml of ethanol and discarded. The mother liquor is combined with the wash solutions, and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated on a rotary evaporator. The residue is stirred under reflux in ethanol for 20 min and then filtered off while still hot. The solid obtained is dried under high vacuum.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH:14]2[CH2:15][C:16](=O)[CH:12]([CH2:13]2)[CH2:11]1>>[CH2:15]1[CH:14]2[C:10]3[C:11]([CH:12]([CH2:13]2)[CH2:16]1)=[N:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]=3[NH2:9]
Reactant: O=C1CC2CCC1C2
Reactant: N#Cc1ccccc1N
Product: Nc1c2c(nc3ccccc13)C1CCC2C1

Procedure:
Anthranilonitrile (ortho-isomer) is allowed to react with norcamphor to obtain 9-amino- 1,4-methano- 1,2,3,4-tetrahydroacridine (Formula VIa). ##STR8##
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C

Procedure:
In a sealed reaction flask 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) was dissolved in 3 mL of anhydrous DMF, to this solution tetrabutylammonium iodide (140 mg, 0.38 mmol) was added followed by N-methylpiperazine (0.127 mL, 1.14 mmol) and the reaction heated at 60° C. for 56 hours. At the end of this time 10 mL of water was added and the resulting solid removed by filtration. The solid was purified by reversed phase HPLC using a phenyl-hexyl reverse phase column with a 30-50% ACN/H2O gradient over 60 minutes. The appropriate peak was concentrated, basified with saturated sodium bicarbonate and extracted twice with ethyl acetate. The extracts were dried with magnesium sulfate, filtered and concentrated to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea as a solid weighing 15.75 mg. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.4 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 6.47 (s, 1H), 4.2 (m, 2H), 3.99 (s, 3H), 2.5-2.2 (m, 9H), 2.11 (s, 3H), 1.99 (m, 2H), 1.27 (s, 9H). LC-MS (ESI) m/z 590 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2].IC.[CH3:25]C([O-])(C)C.[K+]>C1COCC1>[C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH3:25])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.065 g, 0.209 mmol) in THF (1 mL) was added iodomethane (0.59 g, 4.18 mmol), followed by dropwise addition of t-BuOK (1M in THF, 0.63 mL, 6.3 mmol). After 10 min, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to afford the title compound: MS (ES) m/z 325 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=3)=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-chloro-pyridin-4-yloxy)-phenylamine (Example 105) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a beige solid: ES-MS: 368.0 [M+H]+; single peak at tR=9.85 min (System 2); Rf=0.36 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3-chloro-4-fluoro phenyl isocyanate (0.075 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 47 as a colorless solid (0.090 g, 52%). LCMS m/z (%)=405 M+H+ (37Cl, 23) 403 M+H+ (35Cl, 60), 1H NMR (400 MHz, acetone-d6) δ: 8.3 (bs, 1H), 8.1 (bs, 1H), 7.82-7.796 (dd, J1=6.75 Hz, J2=2.58 Hz, 1H), 7.536 (d, J=2.67 Hz, 2H), 7.514 (d, J=2.67 Hz, 2H), 7.43 (d, J=1.57 Hz, 1H), 7.368 (d, J=2.65 Hz, 1H), 7.299 (d, J=1.23 Hz, 1H), 7.136 (t, 1H), 6.079 (d, J=1.69 Hz, 1H), 4.224 (m, 1H), 3.73 (s, 3H), 1.308 (d, J=6.61 Hz, 6H).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[Mg].I[CH2:14][CH3:15].[Cl-].[NH4+]>C(OCC)C.O>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:14][CH3:15])=[CH:4][C:3]=2[O:2]1
Reactant: CCI
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-methylenedioxybenzaldehyde (4.5 g, 30 mmol) of formula 2 prepared in dry diethyl ether is slowly added to an ethereal solution of Grignard reagent prepared from magnesium metal (0.84 g, 35 mmol) and iodoethane (3.0 ml, 40 mmol) and the contents stirred for 1 hour at room temperature. After the completion of the reaction, the mixture is processed by adding saturated aqueous solution of ammonium chloride (10 ml) followed by dilution with water (100 ml), separating the organic layer and extracting the aqueous layer with solvent ether (2×100 ml). The combined organic layer washed with water (2×20 ml) dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1-(3,4-methylenedioxyphenyl) propan-1-ol, a semisolid of formula 3 (5.3 g, 97.5%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH:11]1([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Product: O=C(NC1CCCCC1)C1CCN(Cc2cccc(Br)n2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 6-bromo-pyridine-2-carboxaldehyde and piperidine-4-carboxylic acid cyclohexylamide hydrochloride as in 3.01c: LC-MS A: tR=0.61 min; [M+H]+=382.20.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([CH:12]=O)[C:3]=1[N:14]1[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]1.[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CC(O)C>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]2[C:3]=1[N:14]1[CH2:15][C@@H:16]([CH3:21])[O:17][C@@H:18]([CH3:20])[C@@H:19]1[C:28]1([C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]1=[O:30])[CH2:12]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Solvent: CC(C)O
Product: Cc1noc2c(Cl)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 85 °C

Procedure:
To a solution of 7-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-methyl-1,2-benzoxazole-5-carbaldehyde (Intermediate 375, 35 mg, 0.119 mmol) in IPA was added barbituric acid (16 mg, 0.113 mmol) and the mixture heated at 85° C. for 16 hours. Solvents were evaporated and the residue thus obtained was purified over silica column using a gradient of methanol in chloroform to give product as a solid. Yield: 10 mg (25%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1ccc(CBr)c(Cl)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(Cl)cc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:33].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[C:26]([O:25][C:24]([N:23]([CH3:31])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@H:4]([CH2:3][C:2]([OH:33])=[O:1])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:28])([CH3:27])[CH3:29]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Yield: 69.9 %

Procedure:
A solution of 22.3 (1.25 g, 2.79 mmol, 1.00 equiv) and dipyridinium dichromate (4 g, 10.64 mmol, 4.00 equiv) in 10 mL of DMF was stirred for 15 h at room temperature. The reaction was then quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to afford 2-[(3S)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid (22.4, 900 mg, 70%) as a colourless oil.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].CCN(CC)CC>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)CCCCl)CC1
Yield: 98914.6 %

Procedure:
Ethyl piperazine-1-carboxylate (800 mg, 5.06 mmol) was treated with 4-chlorobutanoyl chloride (856 mg, 6.07 mmol) in anhydrous CH2Cl2 (25 mL) containing Et3N (1.54 kg, 15.17 mmol) at 20° C. for 2 h, and then washed with 1 M HCl(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give ethyl 4-(4-chlorobutanoyl)piperazine-1-carboxylate (1.315 kg, 99% yield). C11H19ClN2O3; pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (2H, q, J=7.2 Hz), 3.62 (2H, t, J=5.6 Hz), 3.58 (2H, m), 3.46 (6H, m) 2.49 (2H, t, J=6.8 Hz), 2.11 (2H, m), 1.25 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 170.1, 155.1, 61.7, 45.2, 44.8, 43.7 (2×), 41.4, 29.8, 27.8, 14.7; ESI-HRMS calcd for C11H20ClN2O3: 263.1162. found: m/z 263.1175 [M+H]+.
Reaction SMILES: [C:1]1(=O)CCCCC1.[OH:8][C:9]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]([OH:17])=[C:11](C)[C:10]=1[OH:19]>>[OH:19][C:10]1[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]([OH:16])[C:12]([OH:17])([CH3:1])[CH:11]=1
Reactant: Cc1c(O)c(O)c(C)c(O)c1O
Reactant: O=C1CCCCC1
Product: CC1=C(O)C(O)=CC(C)(O)C1O

Procedure:
Attempts to form acetals from polyhydric phenols with two or more pairs of ortho-positioned hydroxy groups have been less successful. Soloway in U.S. Pat. No. 2,927,096 describes the preparation of resins from aldehydes and polyhydric phenols, such as 1,2,4,5-tetrahydroxybenzene and pentahydroxy benzene. Dallacker et al in Annalen, Band 719 (1968), pp. 112-118 describe the preparation benzo [1.2-d:4.5-d']bis[1.3] dioxoles of the formula (III) wherein R is hydrogen, methoxy or allyl, by heating the corresponding mono-dioxole (IV) with chlorobromomethane in dimethyl formamide in the presence of potassium carbonate ##STR1## Kaye describes in the 13th Annual Report on Research, Petroleum Research Fund (1968) how reaction of catechol with cyclohexanone in the presence of toluene sulphonic acid in benzene gives only a 49% yield of the acetal, with some alkylation of the aromatic ring. Under the same conditions, no reaction took place between cyclohexanone and 1,2,4,5-tetrahydroxy-3,6-dimethylbenzene. He showed, however, in Abstracts of Research Supported by the Petroleum Research Fund (1968) p. 21 that 1,2,4,5-tetrahydroxy-3,5-dimethylbenzene formed an acetal (V) when heated with dichlorodiphenyl methane. ##STR2##
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>C1(C)C=CC=CC=1>[CH3:24][N:23]([CH3:25])/[C:21](=[N:16]/[C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15])/[CH3:22]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Solvent: Cc1ccccc1
Product: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (0.280 g, 0.000909 mol) in toluene (5 mL) was added dimethylacetamide-dimethylacetal (0.405 mL, 0.00273 mol). The solution was stirred at 95° C. for 4 h. The toluene was removed in vacuo to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide. MS (ESI+) 377.1/379.1.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(=O)(O)[O-].[Na+].C([O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][C:54]=1[O:55]C(=O)C)[C:49](Cl)=[O:50])(=O)C>CC(C)=O.O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:20][CH2:21][N:22]([C:49](=[O:50])[C:48]5[CH:52]=[CH:53][C:54]([OH:55])=[C:46]([OH:45])[CH:47]=5)[CH2:23][CH2:24]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCNCC1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCN(C(=O)c2ccc(O)c(O)c2)CC1
Yield: 39.2 %

Procedure:
The solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (540 mg) in acetone (5 ml) and water (5 ml) was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. To the mixture was added 3,4-diacetoxybenzoyl chloride (308 mg) at pH 6.5-7.0. The mixture was stirred for an hour and evaporated in vacuo to remove acetone. The residue was adjusted to pH 8.5 with a saturated aqueous solution of sodium bicarbonate and then stirred for 2 hours at room temperature. The mixture was adjusted to pH 3.5 with 3N hydrochloric acid and then filtered. The filtrate was subjected to column chromatography on Diaion HP-20 using 5% aqueous isopropyl alcohol as an eluent. The eluate was evaporated in vacuo to remove isopropyl alcohol and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[1-methyl- 4-(3,4 -dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (265 mg).
Reaction SMILES: Cl.CN.[N:4]1([C:9](=[O:29])[CH2:10][C@H:11]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=CN=[CH:5]1.O>C(O)(C)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][C:9]([NH:4][CH3:5])=[O:29])=[CH:19][NH:20]2
Reactant: COc1cccc2[nH]cc([C@@H](CC(=O)n3ccnc3)c3ccccc3)c12
Agent: CN
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CNC(=O)C[C@@H](c1ccccc1)c1c[nH]c2cccc(OC)c12
Temperature: 22 °C
Yield: 98 %

Procedure:
Methylamine hydrochloride (2.04 kg) was added, and the reactor contents were stirred at 22 degrees C. overnight. A 10 mL aliquot of the reactor contents was taken, from which HPLC indicated completion (<1% of (S)-1-Imidazol-1-yl-3-(4-methoxy-1H-indol-3-yl)-3-phenyl-propan-1-one) of the reaction. Cold tap water (64 L) was added, followed by isopropyl alcohol (8.2 kg). The reactor was set up for atmospheric distillation, and the reactor jacket was heated at 85 degrees C. and methylene chloride was removed by distillation until the reactor temperature reached 70 degrees C. The reactor was gradually cooled to 22 degrees C. and the resulting slurry was stirred for one hour. The product was filtered on a Nutsche filter, and the collected solid was washed with water-isopropyl alcohol (1:1) and dried at 70 degrees C. to afford (S)-3-(4-methoxy-1H-indol-3-yl)-N-methyl-3-phenyl-propionamide as an off-white crystalline solid, (7.094 kg, 98% yield). 1H nmr (DMSO-d6): 2.48 (d, 3H, J=4.56 Hz), 2.60-2.90 (m, 2H), 3.69 (s, 3H), 5.05 (t, 1H, J=7.95 Hz), 6.34 (m, 1H), 6.90 (m, 2H), 7.08 (m, 2H), 7.20 (m, 4H), 7.75 (bq, 1H, J=4.56 Hz), 10.8 (bs, 1H). Mp=178-181° C.