Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16].[C:18]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OCC)=[O:31])=[CH:25][CH:24]=1)(=[O:20])[NH2:19]>>[C:18]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:17])[CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[O:31])=[CH:25][CH:24]=1)(=[O:20])[NH2:19]
Reactant: N#Cc1ccccc1OCC(O)CNCCN
Reactant: CCOC(=O)Cc1ccc(OCC(N)=O)cc1
Product: N#Cc1ccccc1OCC(O)CNCCNC(=O)Cc1ccc(OCC(N)=O)cc1

Procedure:
In a similar manner using 2.36 g. of 3-(β-aminoethylamino)-1-(2-cyanophenoxy)-2-propanol and 2.37 g. of ethyl 4-carbamoylmethoxyphenylacetate as starting materials there is obtained 3-β-(4-carbamoylmethoxyphenylacetamido)ethylamino-1-(2-cyanophenoxy)-2-propanol, isolated as its hydrogen oxalate, m.p. 123°-125° C. after crystallisation from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[C:2]([CH:7]=1)[NH2:1]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ccccc1[N+](=O)[O-]
Yield: 101 %

Procedure:
Following General Procedure A, the title compound (548 mg, 95%) was prepared from 2-amino-4-chlorobenzenethiol (441 mg, 2.76 mmol), 1-(bromomethyl)-2-nitrobenzene (398 mg, 1.84 mmol) and K2CO3 (1.27 g, 9.21 mmol) in DMF (20 ml).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:23]([N+:24]([O-])=O)=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:27].C1COCC1>CCO.[Pd]>[CH3:27][C:7]1[C:8]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:11][CH2:10][C:9]=2[CH:22]=[C:23]2[NH:24][C:3](=[O:2])[CH2:4][O:5][C:6]=12
Reactant: COC(=O)COc1c([N+](=O)[O-])cc2c(c1C)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c2c(cc3c1OCC(=O)N3)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a mixture of 967 mg of t-butyl 7-(2-methoxy-2-oxoethoxy)-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 25 ml of EtOH was added 97 mg of 10% palladium on carbon under an argon atmosphere, followed by stirring for 2 hours at normal pressure under a hydrogen atmosphere. To the reaction mixture was added 200 ml of THF, then the catalyst was removed using celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 629 mg of t-butyl 11-methyl-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[Cl:32][CH2:33][CH2:34][CH2:35]Br.[NH4+].[Cl-]>C1COCC1>[C:7]1([C:5]2[N:6]=[C:2]([CH2:1][CH2:35][CH2:34][CH2:33][Cl:32])[O:3][C:4]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: ClCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: ClCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 2-methyl 4,5-diphenyloxazole (7.05 g, 0.3 mol) in 50 mL of dry THF at -78° C. was added 1.1 equivalent of n-BuLi or LDA and stirred for 30 min. To the dark red solution of the anion was added the alkylating reagent 3-chloro-1-bromopropane (1.1 equivalent) and the reaction mixture was allowed to warm to 0° C. over a period of 1 h. The reaction was worked up by adding NH4Cl solution and extracting with ethyl acetate (50mL). Dried over Na2SO4, concentrated and purified by flash chromatography over silica gel using ether/hexane 1:4 as an eluant to give the Formula X compound 6.2 g (66%) as an oil. MS (DCI) m/z 311.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([C:14]([OH:16])=[O:15])=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[S:4][CH:3]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:6]2=[N:7][C:8]3[C:14](=[O:15])[O:16][C:11](=[O:13])[C:9]=3[CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: O=C(O)c1cc2scc(Cl)c2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3c(Cl)csc3cc21
Yield: 89 %

Procedure:
3-Chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid (1.45 g) is heated at 85° to 90° C. for 30 minutes then 90° to 102° C. for 30 minutes in acetic anhydride (7 mL). The reaction is cooled, the solids filtered off and washed with ether to give 1.2 g of 3-chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid anhydride.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]([NH:10][CH2:11][C:12]1([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CC([O-])=O.[Na+]>ClCCl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]([NH:10][CH2:11][C:12]1([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9]
Reactant: O=C(CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CC1(CNC(=O)O[C@@H]2CCCC2=O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound (50) (0.50 g, 1.3 mmol) in dichloromethane (15 mL) was added pyridinium chlorochromate (0.55 g, 2.6 mmol) followed by NaOAc (0.21 g, 2.57 mmol) at room temperature. The resulting reaction was stirred overnight at room temperature (monitored by LC/MS), then filtered. The solid was washed with dichloromethane (2×25 mL) and the combined filtrates were washed with water (2×25 mL), dried over MgSO4 and concentrated in vacuo to provide compound 51 which was used in the next step without further purification. MS (ESI): m/z=388.38 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:39][CH3:40]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:39][CH3:40])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1

Procedure:
(a) In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86 (b)] with 2-chloromethyl-1,4-dimethoxy-naphthalene [J.Org.Chem. (1983), 48(19),3265-3268) there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a pale yellow solid; MS: 534 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([CH3:12])([CH3:11])[S:10][C:6]=2[CH:5]=1)=[O:3].[BH4-].[Na+]>C(O)C>[CH3:1][CH:2]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([CH3:11])([CH3:12])[S:10][C:6]=2[CH:5]=1)[OH:3]
Reactant: CC(=O)c1ccc2c(c1)SC(C)(C)S2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)SC(C)(C)S2
Temperature: 0 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/water, there were obtained 41.8 g of 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working-up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][C:45](Br)=[N:46][CH:47]=1)[CH3:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][C:45]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([CH2:13][CH3:14])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:34][CH3:35])([OH:36])[CH2:1][CH3:2])=[C:7]([CH3:33])[CH:8]=3)[CH2:31][CH3:32])=[CH:16][C:17]=2[CH3:30])=[N:46][CH:47]=1)[CH3:38]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: CCOC(=O)Cc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 53 %

Procedure:
Degassed N,N-dimethylformamide (0.63 mL) was added to (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 52.6 mg, 0.107 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 63 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (0) (62.8 mg, 0.0543 mmol) and potassium phosphate (75 mg, 0.35 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for 13 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (30 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]([O:25]C)=[O:24])[C:12]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:22][C:23]([OH:25])=[O:24])[C:12]2=[O:27])[CH2:28][CH2:29]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CC(=O)O)CN2c1ccccc1
Yield: 81.3 %

Procedure:
A stirred mixture of 2.96 g (7.8 mmol) of methyl 8-(t-butoxycarbonyl)-4-keto-1-phenyl-1.3.8-triazaspiro[4.5]decan-3-acetate, 2.03 g (14.7 mmol) of potassium carbonate, 30 ml of methanol and 10 ml of water was heated under reflux for 2 hours. The mixture was concentrated to about one-third of its original volume, diluted with 20 ml of water and acidified with 2N HCl at 0° C. The mixture was extracted with ethyl acetate and the extracts were washed with water and brine, dried, and concentrated in vacuo. Recrystallization of the residual solid from ethanol afforded 2.47 g (86%) of colorless crystals, mp 200°-201° C.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]([C:23]1([NH2:32])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:18]([O:20][C:21]([C:23]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])[CH3:19]
Reactant: Cc1cc(CO)cc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
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: CCOC(=O)C1(NC(=O)c2cc(CO)cc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 2-cyclobutoxy-5-hydroxymethyl-3-methyl-benzoic acid (410 mg, 1.7 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (425 mg, 1.7 mmol), HATU (760 mg, 2 mmol) in anhydrous DMF (5 mL) is added DIPEA (4354, 2.5 mmol). The resulting solution is stirred at RT overnight. Water (10 mL) is poured into the reaction mixture, and then extracted with EtOAc (3×7 mL). The combined organic layers are concentrated in vacuo. The residue is purified by reverse phase chromatography (gradient elution: 20-100% ACN in water) to give product (285) as colorless oil (70 mg, 10%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14](C#N)[C:15](=[O:19])[NH:16][C:17]=3[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.N>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[NH:16][C:17]=3[CH3:18])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(-n2ccnc2)cc1
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(=O)ccc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of 1,2-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecarbonitrile 21.8 g) in 110 ml of 85% (w/w) sulfuric acid is heated at 205° C. for 19 hours. The reaction mixture is cooled to room temperature, poured into 600 ml of ice, and the resulting solution adjusted to pH 8 with concentrated ammonia. The precipitate is collected and recrystallized from dimethylformamide to give 10.0 g of 5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2(1H)-pyridinone, mp 310°-314° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@H:6]([C:11]#[N:12])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].CCO.[O-]CC.[Na+]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]([C:11]#[N:12])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)[C@H](C#N)CC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(C#N)CC(C)C
Temperature: 80 °C

Procedure:
A reactor was charged with (R)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 22, 49.5 kg) and EtOH (250 L). Sodium ethoxide (21% w/w in EtOH, 79.0 L, 1.1 eq) was added to the mixture, which was heated to 80° C. for 20 h. After completion of the reaction, the mixture was allowed to cool to RT and was neutralized by adding HOAc (12.2 L). Following evaporation of the EtOH, MTBE (150 L) was added to the mixture, and the resulting solution was filtered and evaporated to afford (R/S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 20) in quantitative yield.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:8]([I:21])=[C:9]([C:18]([Cl:20])=[O:19])[C:10]([I:17])=[C:11]([C:15]=1[I:16])[C:12]([Cl:14])=[O:13].O>CC(N(C)C)=O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[C:15]([I:16])=[C:11]([C:12]([Cl:14])=[O:13])[C:10]([I:17])=[C:9]([C:8]=1[I:21])[C:18]([Cl:20])=[O:19])=[O:4]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CCl)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 1 h
Yield: 75 %

Procedure:
At maximally 10° C., 67.7 g (0.6 mol) of chloroacetyl chloride is added dropwise under agitation within 20 minutes to a solution of 119.1 g (0.2 mol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride in 400 ml of dimethylacetamide; the mixture is further stirred for 1 hour under ice cooling and then overnight at room temperature. The reaction mixture is then treated with 6 l of water, the thus-produced precipitate is vacuum-filtered and dissolved in 3.5 l of ethyl acetate. The ethyl acetate solution is washed neutral with 400 ml of saturated NaHCO3 solution and twice with water, dried with Na2SO4, and concentrated under vacuum. The residue is treated with 800 ml of ether and dried under vacuum at 50° C., thus obtaining 100.8 g (75% of theory) of 5-chloroacetamido-2,4,6-triiodoisophthalic acid dichloride, m.p. 254°-256° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]COC)=[CH:9][C:8]([I:15])=[C:7]2[C:3]=1[CH:4](O)[N:5]([C:17]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:6]2=[O:16].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.O>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:15])=[C:7]2[C:3]=1[CH2:4][N:5]([C:17]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:6]2=[O:16]
Reactant: COCOc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1ccccc1)N1Cc2c(Cl)c(O)cc(I)c2C1=O
Yield: 108 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-chloro-5-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (100 mg, 0.21 mmol) was dissolved in nitromethane (4 mL), and the solution was treated with trifluoroacetic acid (0.097 mL, 1.26 mmol) and triethylsilane (0.200 mL, 1.25 mmol). The mixture was added with water and saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-5-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (97.0 mg, yield 98%).
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH:6]2[C:21](=[O:22])[N:8]3[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.[O:29]1CCCC1>O>[C:4]([C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[C:1]([NH:5][CH:6]1[C:21](=[O:22])[N:8]2[C:9]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:28])([OH:29])=[O:23]
Reactant: C1CCOC1
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Solvent: O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1

Procedure:
A solution of 800 mg. (2 mmol.) of t-butyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml. of tetrahydrofuran and 8 ml. of water was cooled in an ice bath. To the solution 660 mg. of Na2S.9H2O were added, and the mixture was stirred and cooled for 10 min. At the end of this period 10 ml. of water were added, and the mixture was extracted with 40 ml. of ethyl acetate. The extract was discarded. The aqueous portion was acidified to pH 4.3 with 1N H2SO4 and then extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated, giving 700 mg. of the title compound. The product was recrystallized from chloroform/cyclohexane; m.p. 178°-179°; ir (nujol) 1770, 1735, and 1680 cm-1 ; nmr (CDCl3 + DMSOd6) δ 1.5 (s, 9, t-Bu), 2.1 (s, 3, CH3), 3.2 and 3.5 (ABq, 2, J = 18 Hz), 5.02 (d, 1, J = 4.5 Hz), 5.82 (dd, 1, J = 4.5 and 9Hz), and 7.4-8 (m, H, ArH).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:7]=1)=[O:4].[C:21](=O)([O:24]C)[O:22][CH3:23]>O1CCCC1.CCCCCC>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1])[CH:11]=[CH:10][C:9]=1[C:21]([O:22][CH3:23])=[O:24])=[O:18]
Reactant: CC(C)(C)C(=O)Nc1cccc(NC(=O)C(C)(C)C)n1
Reactant: COC(=O)OC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 15565.2 %

Procedure:
In a 5 L, 4-necked round bottom flask, immersed in ice-cold ethanol-isopropanol (isopropanol 13%, −15° C.) bath, to a solution of 2,6-bis[(2,2-dimethylpropanoyl)amino]pyridine (J. Am. Chem. Soc. 1986, 108, 3310-3318, 126 g, 454 mmol) in anhydrous tetrahydrofuran (1.5 L) was added 2.66 M solution of n-buthyllithium in hexane (598 mL) dropwise from a dropping funnel (1 L) during the period of 6 h under nitrogen atmosphere (internal temperature was maintained at −15° C.˜−5° C.). The resulting solution was stirred at 0° C. (internal temperature) for 12 h under nitrogen atmosphere. The formation of yellowish precipitate was noticed. Then the suspension was cooled to −15° C., dimethyl carbonate (194 mL, 2.3 mmol) was added in one portion. The reaction solution was stirred at 0° C. for 1 h, quenched with 1.5 L of 1 N aqueous hydrochloric acid, pH value was controlled to ˜4.5 by adding 1 N aqueous hydrochloric acid, then 600 mL of ethyl acetate was added. After the layers were separated, the organic layer was washed with 1 L of 0.2 N aqueous NaOH (1 L) and brine (500 mL). Each aqueous layer was extracted with ethyl acetate (300 mL) twice. Combined organic layer was dried over sodium sulfate (˜300 g) and concentrated. The residue was diluted with diisopropylether (300 mL) and the solution was evaoprated to remove the residual ethyl acetate azeotropically. The residue was dissolved with diisopropylether (360 mL) at 60° C. with gentle stirring, and then the small portion of the crystalline of the desired product (˜5 mg) was added as seed. The formation of a pale yellow precipitate was noticed. The resulting suspension was cooled to room temperature (during the period of 2 h), and stirred at room temperature for 2 h. The suspension was filtered through paper filter, then the cake was washed with diisopropylether (80 mL). The solid was dried under reduced pressure at room temperature for 1 day to give the title compound (120 g, 358 mmol, 79%) as a pale yellow solid.