Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:29][Li]>C1COCC1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:14])([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH3:29])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)O)c(O)c3)ccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(C)(O)COc3ccc(C(=O)O)c(O)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 g (2.6 mmol) of 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoic acid and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 5.3 ml (8.3 mmol) of a solution of methyl lithium in THF (1.6M) are added dropwise at -78° C. and the reaction mixture is stirred for 12 hours at room temperature. It is poured into ice-water, acidified to pH=1 and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is recrystallised in cyclohexane and 900 mg (86%) of the expected product of melting point 170°-171° C. are collected.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:23]CCCCC>CN(C1C=CN=CC=1)C>[CH3:23][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][CH:2]=[CH:11][C:10]=2[NH:12][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2ncccc2c1
Reactant: CCCCCC
Agent: CN(C)c1ccncc1
Product: Cc1cnc2c(NS(=O)(=O)c3ccccc3)cccc2c1
Yield: 61 %

Procedure:
In the similar fashion using route 14 general procedure 27, 3-methylquinoline (Intermediate 31) (130 mg, 0.82 mmol), benzenesulfonyl chloride (170 mg, 0.9 mmol) and DMAP (cat.) gave the title compound (150 mg, 61%) after tituration from n-hexane.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc([N+](=O)[O-])c[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc([N+](=O)[O-])c[nH]c1=O)c1ccccc1

Procedure:
A solution of 100 mg. of 3-amino-5-nitro-2-pyridone in 1.5 ml. of pyridine was cooled and treated with 200 mg. of benzoyl chloride. After 2 hours water was added. The oil that separated was washed with water and triturated with ether. The resultant solid was recrystallized from ethyl acetate to give 3-benzoylamino-5-nitro-2-pyridone, m.p. 267°-268° C.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1.C(N(CC)CC)C.[NH:36]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=[CH:37]1.Cl>ClCCl.C(OC)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][C:20]([N:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:22])[CH2:15][CH2:16]1.[OH2:4].[ClH:1].[ClH:1].[ClH:1].[ClH:1]
Reactant: COc1ccccc1N1CCN(CC(CC(=O)O)c2ccccc2)CC1
Reactant: C1=CC=CNC=C1
Agent: Cl
Solvent: COC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC(CC(=O)N2CCCCCC2)c2ccccc2)CC1
Product: O
Reaction time: 8 h

Procedure:
1,1-Carbonydiimidazole (0.80 g, 4.9 mmol) was added to a solution of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-3-phenylbutanoic acid dihydrochloride (2.00 g, 4.68 mmol) and triethylamine (0.95 g, 9.4 mmol) in dichloromethane (20 ml). After the cessation of gas evolution, a solution of azepine (0.51 g, 5.2 mmol) in dichloromethane (7 ml) was added and stirring continued overnight. The reaction mixture was concentrated under reduced pressure and the crude product chromatographed on silica gel, eluting with ethyl acetate: hexane (5:1) to afford an oil. The oil was dissolved in methyl acetate and acidified with ethereal hydrogen chloride to afford the title compound dihydrochloride hemihydrate as a colourless powder (1.08 g), m.p. 201.5-202.2 (dec.).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:35]C(O)=O)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:34]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=2)=[CH:35][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:44][CH:43]=1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(OC)cc2)cc1
Reactant: O=CN1CCNCC1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=CC(=O)N2CCNCC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
3,41 ml of diphenylphosphoryl azide and 1.09 ml of 1-formylpiperazine were added to a 60 ml of a methylene chloride solution of 3.00 g of 3,3-bis(4-methoxyphenyl)acrylic acid and 2.94 ml of triethylamine. The reaction mixture was then stirred for2 hours at room temperature, after which it was poured into a saturated aqueous solution of sodium bicarbonate and extracted twice with methylene chloride. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 80 ml of methanol, and 40 ml of a 10% w/v aqueous solution of sodium hydroxide were added to the resulting solution. The reaction mixture was stirred for 18 hours at room temperature and then poured into water: it was then extracted twice with methylene chloride. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography through 80 g of silica gel eluted with mixtures of methylene chloride and methanol ranging from 19:1 to 4:1 by volume to give 3.00 g of 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C[O-].[Na+].[Cl-].[NH4+:14]>CO>[ClH:1].[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)(=[NH:14])[NH2:9]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1cc(Cl)ccn1
Reaction time: 2 h

Procedure:
6.93 g (50 mmol) of 4-chloro-2-cyanopyridine in 40 ml of methanol are treated for one hour with 0.27 g (5 mmol) sodium methoxide. After the addition of 3.00 g (56 mmol) of ammonium chloride, refluxing is carried out for two hours. The volatile components are then removed in vacuo. The 2-amidino-4-chloropyridine hydrochloride so obtained is reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][S:50]([N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[CH:44][CH:43]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][S:50]([N:53]6[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]6)(=[O:52])=[O:51])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(S(=O)(=O)CCc2ccc(Br)cc2)CC1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCS(=O)(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-[2-(4-bromo-phenyl)-ethanesulfonyl]-4-methyl-piperazine (94 mg) obtained in Step A in Example 1-D-296 instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-[5-(7-{4-[2-(4-methyl-piperazine-1-sulfonyl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-296) as a colorless solid (11 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>CO>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(CNc2ccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.121 mmol) and MP-CNBH3 (180 mg, 0.360 mmol) in methanol (1 ml) was added acetic acid (6 μl, 0.121 mmol) followed by 3-chlorobenzaldehyde (15 μl, 0.133 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. RT: 3.09 min, MI: 539, Method: 2; 1H NMR (DMSO, 300 MHz): 8.47 (s, 1H), 7.90 (2H, d), 7.50-7.27 (m, 8H), 6.92 (d, 1H), 6.84 (d, 2H), 6.74 (d, 2H), 4.42 (s, 2H), 4.30 (t, 2H), 3.37 (t, 2H), 3.26 (s, 4H), 2.03 (s, 4H).
Reaction SMILES: C(N)(C)C.C([Li])CCC.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>C1COCC1.O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=2)([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of isopropylamine (1.53 ml, 10.94 mmol) in THF (30 ml) at −78° C. was added n-butyllithium (4.38 ml of a 2.5M solution in hexanes, 10.938 mmol). After 10 minutes, a solution of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester in THF (12 ml) was added. After a further 1 hour, a solution of 4-chlorobenzyl chloride (1.84 g, 11.4 mmol) in THF (5 ml) was added and the solution warmed to room temperature over 15 hours. Water (150 ml) was added and the aqueous phase extracted with diethyl ether (150 ml). The organic phase was dried over magnesium sulphate and concentrated to give a crude solid that was purified by recrystallisation from diethyl ether/hexane in two batches to give the product as a white solid (2.650 g, 83%). LC-MS (LCT2) m/z 357 [M+Na+], 235 [M-Boc]+, Rt 8.02 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[S:12](N)(N)(=[O:14])=[O:13]>COCCOCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][S:12](=[O:14])(=[O:13])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethylene glycol dimethyl ether (350 ml) solution of 2-Amino-5-Nitrophenol (40 g) and sulfamide (25 g) was added dropwise to refluxing diethylene glycol dimethyl ether (100 ml) over a period of 50 minutes. Mixture was stirred and refluxing continued 15 minutes, then cooled to room temperature. Solvent was evaporated off, and 500 ml of 1N hydrochloric acid was added. Reaction mixture was extracted with diethyl ether, extract was dried over magnesium sulfate and solvent was removed in vacuo. Crude product was purified by the column chromatography on silica gel (2% Methanol-Ethyl acetate) to give the desired intermediate, 10.5 g.
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]([S-:4])=[S:3].[Na+].[CH3:12]I>CO>[O:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]([S:4][CH3:12])=[S:3]
Reactant: CI
Reactant: S=C([S-])OC1CCCCC1
Agent: [Na+]
Solvent: CO
Product: CSC(=S)OC1CCCCC1

Procedure:
3 g (0.015 mol) of sodium cyclohexyl xanthate is dissolved in 50 ml of dried methanol and heated to reflux with 10.7 g (0.075 mol) of methyl iodide for 1 hour. After cooling, the reaction solution is evaporated by using a rotary evaporator, dissolved in ether/water (50/50), the ether phase being separated and dried with sodium sulfate, purified with active carbon/bleaching earth, and evaporated with the aid of a rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH:12]=[CH:13][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:14])=[O:11].[Cl:15][CH2:16][C:17](Cl)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:15][CH2:16][C:17]([O:14][C:4]1[C:3]([O:2][CH3:1])=[C:8]2[C:7]([CH:13]=[CH:12][C:10](=[O:11])[O:9]2)=[CH:6][CH:5]=1)=[O:18].[C:10]([O:9][CH2:8][CH3:7])(=[O:11])[CH3:12]
Reactant: COc1c(O)ccc2ccc(=O)oc12
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(C)=O
Product: COc1c(OC(=O)CCl)ccc2ccc(=O)oc12
Yield: 90 %

Procedure:
1.8 g of hydrangetin (0.01 mole) is acetylated with 1.35 g of 2-chloroacetyl chloride (0.012 mole) by heating at 80° C. in dimethylformamide in the presence of sodium carbonate. After vacuum filtration and evaporation, 7-(2′-chloroacetyloxy)-8-methoxycoumarin (compound A) is isolated by crystallization in ethyl acetate (yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38]([O:42]C(=O)CN)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NOC(C)(C)C

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, O-(tert-butyl)hydroxylaminehydrochloride was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CON(Cc2ccc(NC(=O)C3CC3)cc2Cl)C1=O
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To a stirred solution of 3.0 grams (0.012 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone and 1.2 grams (0.012 mole) of triethylamine in 30 ml of tetrahydrofuran was added dropwise 1.4 grams (0.013 mole) of cyclopropanecarboxylic acid chloride in 20 ml of tetrahydrofuran. During the addition the reaction mixture was cooled in an ice-water bath. Upon completion of addition the reaction mixture stirred for 16 hours; then was concentrated under reduced pressure to a residual solid. The solid was dissolved in 250 ml of methylene chloride. The solid was washed with water, which caused the precipitation of a solid that was insoluble in the liquid phases. The solid was removed by filtration. The organic phase was separated and washed with three 100 ml portions of water. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual solid. Both solids collected were subjected to thin layer chromatography and were determined to be the same material. The solids were combined and recrystallized from ethyl acetate/acetonitrile to give 2.5 grams of 2-[2-chloro-4-(cyclopropylcarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 191°-193° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH2:6])[CH3:2].[C:17]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:24])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCCCCCCSC[C@H](N)C(=O)OCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 20 ml of HMPA were dissolved 5.9 g of S-heptyl-L-cysteine ethyl ester and 5.5 g of 2-bromopropionic acid t-butyl ester. A 3.4 ml quantity of triethylamine was added to the solution. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was separated and purified by silica gel column chromatography (a 1:3 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 2.8 g.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
Sodium hydride (1.35 g of 80% in mineral oil, 45.0 mmol) was added to a stirred solution of phenol (4.26 g, 45.3 mmol) in DMF (30 mL) at 0° C., under nitrogen. The mixture was stirred at room temperature for 3 h, treated with 3,5-dibromopyridine (4.0 g, 16.9 mmol) and heated at 100° C. for 48 h. The reaction mixture was cooled to room temperature, poured into a mixture of water (100 mL) and 5M sodium hydroxide (10 mL), and extracted with ether (3×60 mL). The combined ether extracts were dried (Na2SO4), filtered, and rotary evaporated to a pale yellow semi-solid (4.9 g). This was chromatographed on a silica gel (200 g) column with hexane/ethyl acetate/chloroform (8:1:1, v/v) as eluent to give 2.86 g (68% yield) of a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[O:19]1[CH:23]=[N:22][N:21]=[C:20]1[C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:27]3[CH:26]=[CH:25][C:24]([C:20]4[O:19][CH:23]=[N:22][N:21]=4)=[CH:29][CH:28]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Oc1ccc(-c2nnco2)cc1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nnco4)cc3)CC2)CC1

Procedure:
According to the procedure described for example 1, the title compound had been synthesized from cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone and 4-(1,3,4-oxadiazole-2-yl)-phenol. MS (m/e): 399.1 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:9][S:8][CH:7]=[N:6][C:5]=1[C:10]([O:12]CC1C=CC(OC)=CC=1)=[O:11].CC1CSC=NC=1C(OCC(Cl)(Cl)Cl)=O.[C:37]([O:42][CH2:43][C:44]1[CH2:49][S:48][CH:47]=[N:46][C:45]=1[C:50]([O:52]COC)=[O:51])(=[O:41])[CH:38]([CH3:40])[CH3:39].[N:56]([CH:59]([O:63][CH3:64])[C:60](Cl)=[O:61])=[N+:57]=[N-:58]>>[CH3:1][O:2][CH2:3][C:4]1[CH2:9][S:8][C@@H:7]2[C@@:59]([N:56]=[N+:57]=[N-:58])([O:63][CH3:64])[C:60](=[O:61])[N:6]2[C:5]=1[C:10]([O-:12])=[O:11].[C:37]([O:42][CH2:43][C:44]1[CH2:49][S:48][C@@H:47]2[C@@:59]([N:56]=[N+:57]=[N-:58])([O:63][CH3:64])[C:60](=[O:61])[N:46]2[C:45]=1[C:50]([O-:52])=[O:51])(=[O:41])[CH:38]([CH3:39])[CH3:40]
Reactant: COC(N=[N+]=[N-])C(=O)Cl
Reactant: COCC1=C(C(=O)OCc2ccc(OC)cc2)N=CSC1
Reactant: COCOC(=O)C1=C(COC(=O)C(C)C)CSC=N1
Agent: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N=CSC1
Product: COCC1=C(C(=O)[O-])N2C(=O)[C@](N=[N+]=[N-])(OC)[C@H]2SC1
Product: CO[C@@]1(N=[N+]=[N-])C(=O)N2C(C(=O)[O-])=C(COC(=O)C(C)C)CS[C@@H]21

Procedure:
Following the procedures described in Example 40 p-methoxybenzyl 5-methoxymethyl-6H-1,3-thiazine-4-carboxylate, 2,2,2-trichloroethyl 5-methyl-6H-1,3-thiazine-4-carboxylate or methoxymethyl 5-isobutyryloxymethyl-6H-1,3-thiazine-4-carboxylate are reacted with 2-azido-2-methoxyacetyl chloride to obtain p-methoxybenzyl dl-3-methoxymethyl-7β-azido-7α-methoxy-3-cephem-4-carboxylate, 2,2,2-trichloroethyl d1-3-methyl-7β-azido-7α-methoxy-3-cephem-4-carboxylate and methoxymethyl dl-3-isobutyryloxymethyl-7β-azido-7α-methoxy-3-cephem-4-carboxylate, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:33]([C:37]1[CH:46]=[CH:45][C:40]([O:41][CH2:42][CH2:43][Cl:44])=[CH:39][CH:38]=1)(=[O:36])(=[O:35])[NH2:34]>C1(C)C(C)=CC=CC=1>[ClH:44].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:43][CH2:42][O:41][C:40]2[CH:39]=[CH:38][C:37]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:46][CH:45]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: NS(=O)(=O)c1ccc(OCCCl)cc1
Solvent: Cc1ccccc1C
Product: Cl
Product: NS(=O)(=O)c1ccc(OCCN(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1
Yield: 43.2 %

Procedure:
A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine (13.6 g.), 2-(4-sulfamoylphenoxy)ethyl chloride (4.8 g.) and dry xylene (50 ml.) was boiled under reflux for 12 hours. The solution was cooled and the precipitated solid removed by filtration, the filtrate then being evaporated in vacuo to dryness and taken up into diethyl ether. Insoluble material was removed from the ethereal solution by filtration, and the filtrate treated with ethereal hydrogen chloride, which resulted in the precipitation of a yellow solid. The latter was collected by filtration and recrystallized from a methanol/isopropanol mixture giving N-[2-(3,4-dibenzyloxyphenyl)ethyl]-N-[2-(4-sulfamoylphenoxy)ethyl] benzylamine hydrochloride (5.8 g.), m.p. 178°-181° C.