Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].Cl[C:6]1[N:7]([CH2:14][CH2:15][C@H:16]([OH:29])[CH2:17][O:18]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[N:10]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([O:18][CH2:17][C@H:16]3[O:29][C:6]4=[N:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][N:7]4[CH2:14][CH2:15]3)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Agent: CC[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
An ethanol solution (25.00 ml) of 20% sodium ethoxide was added to an ethanol solution (250 ml) of toluene-4-sulfonic acid (S)-4-(2-chloro-4-nitro-imidazol-1-yl)-2-hydroxybutyl ester (25.00 g), and the mixture was stirred at room temperature for 30 minutes. 4-(4-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (19.63 g) and tripotassium phosphate (13.61 g) were added to the reaction mixture, followed by heating under reflux for 4 hours. The reaction mixture was then concentrated under reduced pressure, and water was added to the residue, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=0:1) and concentrated under reduced pressure. Sodium hydride (3.08 g) was added to a dimethylformamide solution (269 ml) of residue and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=0:1) to afford the title compound as a yellow powder (16.57 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[OH:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-amino-2-indanol (2.0 g) is suspended in 100 mL CH2Cl2 and at RT combined with acetic anhydride (1.27 mL). The reaction mixture is stirred for 1 h at RT. After the reaction has ended the solvent is eliminated using the rotary evaporator and the crude product (HPLC-MS: tRet.=0.81 min; MS (M+H)+=192) is used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH2:8][C:9](=[O:16])[CH:10]([C:12]([O:14][CH3:15])=[O:13])[O:11][C:5]=2[CH:4]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:23][CH2:22][CH2:21][CH2:20][C:10]1([C:12]([O:14][CH3:15])=[O:13])[C:9](=[O:16])[CH2:8][CH2:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11]1
Reactant: COC(=O)C1Oc2cc(OC)ccc2CCC1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(CCCCl)Oc2cc(OC)ccc2CCC1=O
Reaction time: 5 h
Yield: 93.1 %

Procedure:
A solution of 15 g of methyl 3-(4-methoxy-2-methoxy-carbonylmethyloxyphenyl)propionate in 200 ml of toluene is added dropwise to a suspension of 5.6 g of 60% oily sodium hydride in 200 ml of toluene to which 0.4 ml of tert-butanol is added, for a period of 8 hours with heating under refluxing. The reaction mixture is heated under refluxing for 30 minutes and allowed to stand overnight, and then poured into ice water containing 10 ml of acetic acid. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=4:1) to give 9.5 g of methyl 8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil. A mixture of 7.4 g of methyl 8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, 10.9 g of 1-bromo-3-chloropropane, 1.5 g of potassium iodide, 10 g of anhydrous potassium carbonate and 300 ml of acetonitrile is heated under refluxing with stirring for 5 hours. After cooling, the inorganic substances are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=8:1) to give 9 g of methyl 2-(3-chloropropyl)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as an oil. In 100 ml of methanol is dissolved 9 g of methyl 2-(3-chloropropyl)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, and 0.6 g of sodium borohydride is added in small portions to the solution under ice-cooling with stirring. The reaction mixture is concentrated under reduced pressure, and the residue is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure, and the residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1) to give 3.3 g of methyl trans-2-(3-chloropropyl)-3-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil from the first fraction eluted.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 123.1 %

Procedure:
A solution of 5-fluor-2-nitrobenzoic acid (2.6 g, 14.1 mmol, Aldrich Chemical Co., Milwaukee, Wis.) and phenol (1.5 g, 15.5 mmol, Aldrich Chemical Co., Milwaukee, Wis.) in DMF (70 mL) was treated with K2CO3 (5.9 g, 42.4 mmol) and heated to 120° C. for 6 hours. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 34A (4.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O>[Pd].O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC=Cc1cccc(F)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C(O)CCCc1cccc(F)c1
Yield: 101.2 %

Procedure:
Hydrogenate a mixture of 4-(3-fluoro-phenyl)-but-3-enoic acid (22 g, 122 mmol), concentrated sulfuric acid (24 ml), and 5% palladium on carbon (3.58 g) in tetrahydrofuran (470 ml) at 60 psi at room temperature overnight. After filtration of the catalyst, remove most of the tetrahydrofuran by rotary evaporation, dilute the residue with ether, wash with water (2×), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (22.50 g, 100%). NMR (400 MHz, CDCl3): δ 1.98 (m, 2H), 2.38 (t, 2H), 2.65 (t, 2H), 6.88 (m, 2H), 6.96 (d, 1H), 7.23 (m, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[CH:29]1[O:31][CH2:30]1>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=2)[CH2:30][CH:29]([OH:31])[C:28]([F:33])([F:32])[F:27])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CC(C)(C)Oc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
The N-(3-phenoxyphenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amine (0.270 g, 0.78 mmol) product from EX-654B was dissolved in 2 mL of acetonitrile. Ytterbium triflate (16 mg, 0.026 mmol) was added in 0.5 mL of acetonitrile, and the mixture was stirred under nitrogen. 1,1,1-Trifluoro-2,3-epoxypropane (0.105 g, 0.94 mmol) was added, the vial was sealed and heated to 45° C. After 24 h, TLC analysis showed 50% conversion, so additional 1,1,1-trifluoro-2,3-epoxypropane (88.6 mg, 0.79 mmol) was added and heating continued for an additional 24 h. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (1.5-7% ethyl acetate). Fractions were pooled based on TLC analysis to give 150 mg (42%) of the desired 3-[(3-phenoxy-phenyl)[[3-(1,1-dimethylethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear, colorless oil, and an additional 60 mg (17%) was obtained as an amber oil. HRMS calcd. for C26H28F3NO3: 460.2100 [M+H]+, found: 460.2103. 1H NMR (C6D6) δ 6.78-7.08 (m, 9H), 6.68 (d, 1H), 6.55 (t, 1H), 6.43 (dd 1H), 6.34 (dd, 1H), 4.23 (s, 2H), 3.81 (m, 1H), 3.48 (dd, 1H), 3.24 (m, 1H), 2.25 (br s, 1H), 1.07 (s, 9H). 19F NMR (C6D6) δ −78.92 (d, 3F).
Reaction SMILES: N(C1N(CC(C)C)C(=O)N(C)C(=O)C=1)N.ClC1C=C2C(=CC=1)NC=C2C=O.C(C1C=C(C=O)N(C)C=1)(=O)C.[C:39]([C:42]1[CH:43]=[C:44]([C:48]2[N:49]([CH2:64][C:65]3[C:73]4[C:68](=[CH:69][CH:70]=[C:71]([Cl:74])[CH:72]=4)[NH:67][CH:66]=3)[N:50]=[C:51]3[C:56]=2[C:55](=[O:57])[N:54]([CH3:58])[C:53](=[O:59])[N:52]3[CH2:60][CH:61]([CH3:63])[CH3:62])[N:45]([CH3:47])[CH:46]=1)(=[O:41])[CH3:40].[BH4-].[Na+]>C1COCC1>[Cl:74][C:71]1[CH:72]=[C:73]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:64][N:49]1[C:48]([C:44]2[N:45]([CH3:47])[CH:46]=[C:42]([CH:39]([OH:41])[CH3:40])[CH:43]=2)=[C:56]2[C:51]([N:52]([CH2:60][CH:61]([CH3:63])[CH3:62])[C:53](=[O:59])[N:54]([CH3:58])[C:55]2=[O:57])=[N:50]1
Reactant: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1
Agent: CC(=O)c1cc(C=O)n(C)c1
Agent: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Agent: O=Cc1c[nH]c2ccc(Cl)cc12
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(C)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Temperature: 80 °C

Procedure:
This compound was made in two steps following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. The isolated 3-(4-acetyl-1-methyl-1H-pyrrol-2-yl)-2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was treated sodium borohydride in anhydrous THF and heated at 80° C. for 1 h and the product was isolated by aqueous workup. The presence of alcohol peak (δ 64.8 ppm)was confirmed by 13C NMR (CDCl3)— no ketone peak at (δ 193.5 ppm).
Reaction SMILES: C(OC([N:11]1[C:15]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[C:16]2=[O:33])[C:14](=[O:34])[N:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:12]1=[O:40])=O)C1C=CC=CC=1.C(O)(=O)C.C(O)C>[Pd].COCCOC>[CH2:38]([O:37][C:35]([N:13]1[C:14](=[O:34])[C:15]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[C:16]2=[O:33])[NH:11][C:12]1=[O:40])=[O:36])[CH3:39]
Reactant: CCOC(=O)N1C(=O)N(C(=O)OCc2ccccc2)C2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)N1C(=O)NC2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A mixture of 3-benzyloxycarbonyl-1-ethoxycarbonyl-1'-(3,4-dichlorobenzyl)spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.7 g.), 10% w/w palladium on carbon (0.1 g.), acetic acid (0.3 ml.), ethanol (25 ml.) and 1,2-dimethoxyethane (50 ml.) was hydrogenated at atmospheric pressure for 2 hours. The mixture was separated by filtration through diatomaceous earth and the filtrate was evaporated. The residual oil solidified on treatment with a few drops of toluene. The solid obtained was recrystallised from ethyl acetate/petrol 60-80 to give 1-ethoxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.7 g.), 176°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[C:6]([O:5][C:1]([NH:2]/[N:3]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=N/NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 80 %

Procedure:
To a solution of t-butyl carbazate (25.5 g, 193 mmol) in THF (60 ml) was added 47% ethyl glyoxylate in toluene (polymer type) (46.1 g, 212 mmol), and stirred at 60° C. for minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The resulting solid was washed with a mixed solvent of hexane:ethyl acetate=5:1 to give 33.9 g of Compound (X-1) (yield: 80%) as colorless solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[Ca+2].[OH-].S(=O)(=O)(O)[OH:17]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:17]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Reaction time: 6 h

Procedure:
1.77 kg (10 mol) of 2,3,4-trifluoronitrobenzene and 1.56 kg (21-mol) of calcium hydroxide are heated to 70° C. in 5 l of water and the mixture is well stirred. The reaction is finished after about 6 h, as can be detected by gas chromatography. The mixture is acidified to pH 1.5 with 70% strength sulfuric acid and worked up as described in Examples 1 and 2 (the alkaline solution can also be filtered from inorganic salts at 60° C. before acidification). 1.40 kg of yellow 2,3-difluoro-6-nitrophenol are isolated; a residual content of 2,3-difluoro-4-nitrophenol cannot be detected. The yield corresponds to 80% of theory.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:11]#[N:12].O>C(OCC)C>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:11][NH2:12]
Reactant: N#Cc1ccc(OCC(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCc1ccc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
1.40 g of lithium aluminum hydride was suspended in 50 ml of diethyl ether, and a solution of 8.00 g of 3-fluoro-4-(2,2,2-trifluoroethoxy)benzonitrile in ml of diethyl ether was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes and subsequently, 10 ml of water was added dropwise over 30 minutes. The insoluble matter was removed by filtration. The ether layer was dried. Diethyl ether was evaporated under reduced pressure to give 7.54 g of crude 3-fluoro-4-(2,2,2-trifluoroethoxy)benzylamine as an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([Cl:17])=[O:14]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dry 1-hydroxy-2-naphthoic acid (50 gms., 0.266 mole) was suspended in 350 ml. dry benzene in a flame-dried 1 liter 1-neck round bottom flask under an air condenser and drying tube. Thionyl chloride (31.7 gms., 0.266 mole) was added in one portion followed by 1.5 ml. dry N,N-dimethylformamide. The reaction mixture was stirred magnetically 2-3 days at room temperature. Insoluble material (6.5 gms.) was removed by filtration, and the yellow-tan filtrate was evaporated to dryness to give pale yellow 1-hydroxy-2-naphthoyl chloride, m. p. 87°-88° C. Chilled anhydrous methanol (100 ml.) was added quickly to the solid chloride in an exothermic reaction. The partial solution was heated about 5 minutes on the steam bath under a drying tube then allowed to cool. The suspension was chilled and the solid was collected to give 43 gms. (92% by weight) of 1-hydroxy-2-methyl naphthoate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[CH:26][CH:25]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[CH:28][CH:29]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOC(=O)CCCc1ccc(O)cc1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CCCC(=O)OCC[Si](C)(C)C)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a stirred solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20 mmol) and 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)butanoate (55 mg, 0.20 mmol) in dry THF (4 mL) at 0° C. (ice/water bath), under nitrogen, was added ADDP (102 mg, 0.40 mmol) followed by nBu3P (100 μL, 0.40 mmol), and the mixture stirred with slow warming to rt over 64.5 hours. The mixture was then concentrated under vacuum and the solid residue partitioned between DCM (5 mL) and water (5 mL) using a hydrophobic frit. The layers were separated and the aqueous layer re-extracted with DCM (5 mL) and the combined organic layer reduced. Purification by SPE (silica, 5 g Cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 7.5:1) afforded the title compound (42 mg).
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.[Br:11]N1C(C)(C)C(=O)N(Br)C1=O.CO.C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:10]1[N:2]2[C:3]([C:4]([NH2:7])=[N:5][CH:6]=[N:1]2)=[CH:8][CH:9]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2cccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnn2c(Br)ccc12
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
A stirred solution containing pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (21.0 g, 0.157 mol) in anhydrous DMF (200 mL) was cooled to −20° C. and 1,3-dibromo-5,5-dimethylhydantoin (22.4 g, 0.078 mol) was added portionwise over ˜45 minutes. The reaction was stirred for another 45 minutes and monitored for completion by TLC (silica gel, GHLF, 5% CH3OH/CH2Cl2). Saturated Na2SO3 solution (300 mL) was added, the resulting suspension was stirred and the solids were collected by suction filtration. The filter cake was washed with water, dried by suction and then partitioned between ethyl acetate (1 L) and 5% sodium carbonate solution (1 L). The layers were separated, the organic layer was washed with fresh sodium carbonate solution and dried over magnesium sulfate. The filtrate from the work-up was also extracted and combined with the main batch then filtered through a pad of Magnesol and concentrated in vacuo to afford crude mono-bromide, KRAM 206-3-1, 29.9 g, 90% yield. Trituration of a 21.5 g quantity of the crude mono-/di-bromo product in hot ethyl acetate (300 mL, 70° C.) provided colorless solids (12.3 g) containing only ˜2% of the di-brominated side-product. 1H-NMR (CD3OD): δ 7.84 (s, 1H), 6.95 (d, 1H, J=4.7 Hz), 6.71 (d, 1H, J=4.7 Hz), 4.89 (s, 3H, —NH2+H2O); MS: LC/MS (+esi), m/z=213.1 [M+H].
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH2:14][S:15][C@@H:16]2[CH:27]([NH2:28])[C:26](=[O:29])[N:17]2[C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].F[C:31]1[NH:32][CH:33]=[C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[N:35]=1>C(#N)C>[CH3:12][C:13]1[CH2:14][S:15][C@@H:16]2[CH:27]([NH:28][C:31]3[NH:32][CH:33]=[C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:41])([F:42])[F:43])[N:35]=3)[C:26](=[O:29])[N:17]2[C:18]=1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: O=C(NCCc1c[nH]c(F)n1)C(F)(F)F
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc(CCNC(=O)C(F)(F)F)c[nH]3)[C@H]2SC1
Yield: 71.6 %

Procedure:
A mixture of t-butyl 3-methyl-7-aminoceph-3-em-4-carboxylate toluene-p-sulphonate (0.442 g.) and 2-fluoro-4-(2-trifluoroacetylaminoethyl)imidazole (0.45 g.) was stirred in acetonitrile (dried over molecular sieve, 10 ml.) at 70°-75° for 1.5 hours. The mixture was filtered and the filtrate purified on silica gel (500 g.) eluted with methylene chloride containing 1%, 2%, 3%, 4% and finally 5% v/v methanol. The relevant fractions were combined to give t-butyl 3-methyl-7-[4-(2-trifluoroacetylaminoethyl)imidazol-2-yl]aminoceph-3-em-4-carboxylate (0.34 g.) which was used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].O1CCCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.[H-].CC(C)C[Al+]CC(C)C>CC1C=CC=CC=1.CO>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:11]=[O:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirred solution of 8 parts of (-)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 225 parts of tetrahydrofuran were added 7.2 parts of 1,1'-carbonylbis[1H-imidazole]. After stirring for 1 hour at room temperature, the whole was cooled to -65° C. and 84 parts of a solution of bis(2-methylpropyl)aluminum hydride 1.5M in methylbenzene were added dropwise during a 10 minutes-period. Upon completion, stirring was continued for 15 minutes at -65° C. After the addition of 16 parts of methanol, the reaction mixture was poured onto water. The whole was acidified and the product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6.6 parts (65%) of (-)-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde as a residue; [α]D =-97.96° (c=1% in CH3OH) (intermediate 50).