Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.P(Br)(Br)[Br:25]>C(Cl)Cl.O>[Br:25][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Solvent: O
Solvent: ClCCl
Product: BrCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of [4-(spiro[indene-1,4′-piperidine]-1′-ylmethyl)phenyl]methanol (1.5 g, 4.91 mmol) in DCM (50 mL) is added phosphorus tribromide (0.667 mL, 6.8 mmol). The reaction mixture is stirred for 15 minutes at 0° C. The reaction mixture is diluted with water (100 mL) at 0° C. and extracted with DCM (2×200 mL). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as an off white solid (1.1 g, 61%). ESI/MS m/z 369 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[OH-].[K+].Cl>O1CCCC1.CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7]
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
Ethyl (2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.49 g) was dissolved in a mixed solvent of tetrahydrofuran (8 mL)-methanol (8 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.25 g) in water (4 mL)) was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained amorphous solid was crystallized from ethyl acetate-hexane to give the title compound (256 mg, yield: 56%) as pale-yellow crystals. MS: 422 (MH+). melting point >240° C. (decomposition).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([N:6]1[C:14]2[CH:13]=[C:12]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])[CH:11]=[C:10]([C:24]([O:26]C)=[O:25])[C:9]=2[CH:8]=[N:7]1)[CH3:5]>C(O)C>[CH3:5][CH:4]([N:6]1[C:14]2[CH:13]=[C:12]([S:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])[CH:11]=[C:10]([C:24]([OH:26])=[O:25])[C:9]=2[CH:8]=[N:7]1)[CH3:3]
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)cc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(S(=O)(=O)N3CCOCC3)cc21

Procedure:
Sodium hydroxide (0.980 mL, 0.980 mmol) was added to a solution of methyl 1-(1-methylethyl)-6-(4-morpholinylsulfonyl)-1H-indazole-4-carboxylate (90 mg, 0.245 mmol) in ethanol (30 mL) and heated at reflux for 1 hour. The solvent was removed in vacuo and the residue suspended in water (20 mL). The contents were acidifed by addition of acetic acid, and extracted with DCM (4×30 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was collected as 90 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.63-1.78 (m, 6H), 3.02-3.24 (m, 4H), 3.67-3.88 (m, 4H), 5.00 (dt, J=13.20, 6.66 Hz, 1H), 8.21 (s, 1H), 8.31 (s, 1H), 8.71 (s, 1H), LCMS(ES) [M+H]+ 354.2
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=O)[CH2:4][OH:5].[C:10]([O:14][CH3:15])(=[O:13])C=C.OS(O)(=O)=O>CCOCC.CS(C)=O>[CH3:15][O:14][C:10]([CH:9]1[C:4](=[O:5])[CH2:3][O:7][CH2:8]1)=[O:13]
Reactant: CCOC(=O)CO
Reactant: C=CC(=O)OC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)C1COCC1=O
Temperature: 25 °C

Procedure:
To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0° C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:22][C:13]1[CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:17][C:12]=1[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)c(F)c1
Yield: 64.5 %

Procedure:
2′-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (0.30 g, 2.07 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.5 g, 1.98 mmol), 2M Na2CO3 (12 mL) and Pd(PPh3)4 (20 mg, 0.02 mmol) in DME (12 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H, Ja=8.0 Hz, Jb=1.5 Hz), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.47 (d, 2H, J=7.1 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.94 (bs, 1H), 3.10 (s, 3H); LRMS (ESI), m/z 267 (M+H).
Reaction SMILES: C(=O)(O)[O-].[K+:5].[C:6]([O:13]CC)(=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].O.C(=O)=O>CC(C)=O>[C:7]([O:9][CH2:10][CH3:11])(=[O:8])[C:6]([O-:13])=[O:12].[K+:5]
Reactant: CCOC(=O)C(=O)OCC
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(=O)[O-]
Temperature: 40 °C
Yield: 96 %

Procedure:
A suspension of potassium bicarbonate (100 g; 1.00 mols) in diethyl oxalate (146.1 g; 1.00 mols) is added with water (26 g) and heated at a temperature of 50÷55° C. for 6÷8 hours until carbon dioxide evolution ceases. The suspension is cooled to 40° C., added with acetone (250 mL) and cooled to 15÷20° C. The resulting solid is filtered, washed with acetone (2×25 mL) and dried at 50° C. under vacuum to obtain potassium monoethyl oxalate (150.0 g, 99% purity, yield 96%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([O:12][C:13](OCC)=[CH2:14])[CH3:11].CCO>[O-]CC.[Na+].CCOC(C)=O>[C:3]([C:2](=[C:10]([O:12][CH2:13][CH3:14])[CH3:11])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=C(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)=C(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A 5 L 4-neck flask equipped with a mechanical stirrer, condenser, thermowell, addition funnel and N2 inlet was charged with ethyl acetoacetate (493.1 g, 483 mL, 3.7931 mol, 1.0 equiv) and sodium ethoxide (3.1 g, 0.046 mol, 1.2 mol %). Ketene diethylacetal (880.0 g, 1000 mL, 7.5862 mol, 2.0 equiv) was added over 1 hr maintaining the reaction temperature at <22° C. by external cooling. When addition was complete, the reaction mixture was heated at 85° C.±5° C. for 7.5 hr. The yellow brown reaction mixture was cooled to room temperature and stirred overnight. Much of the lower boiling components [EtOH, EtOAc, Me(OEt)3] were stripped on a roto-evaporator (bath temperature ˜65° C.). The residual yellow-orange oil was distilled, collecting the fraction with bp 100-107° C. (1.8-2.1 Torr) to give 675.2 g (89%) of product as a yellow liquid.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+].[O:38]1[CH2:41][C:40](=O)[CH2:39]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[O:38]1[CH2:41][CH:40]([NH:24][CH:21]2[CH2:20][CH2:19][CH:18]([O:17][C:8]3[C:7]4[C:6]5[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=5[S:13][C:12]=4[N:11]=[CH:10][N:9]=3)[CH2:23][CH2:22]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reactant: O=C1COC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(NC5COC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (400 mg, 0.90 mmol, 1.00 equiv) in DCM (10 mL) was added concentrated hydrochloric acid (0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 10 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 5 mL of MeOH (5 mL), oxetan-3-one (288 mg, 4.00 mmol, 10.00 equiv) was added and the reaction was stirred for around 30 min. Then NaBH3CN (76 mg, 1.21 mmol, 3.00 equiv) was added and the resulting solution was stirred overnight at 35° C. The reaction was then quenched by the addition of cooled brine, extracted with DCM (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (110 mg) was purified by preparative HPLC under the following conditions (Waters): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 45.0% in 12 min, up to 95.0% in 2 min, down to 5.0% in 2 min); UV detection at 254/220 nm. Flow rate: 20 mL/min. The desired 2-[(3R)-12-([4-[(oxetan-3-yl)amino]cyclohexyl]oxy)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (90 mg) was obtained as a white solid. MS: m/z 403 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 5.24-5.35 (m, 3H), 4.85 (t, 2H, J=6.9 Hz), 4.46 (t, 2H, J=6.9 Hz), 4.06-4.11 (m, 1H), 3.80-3.85 (m, 1H), 2.95-3.21 (m, 3H), 2.78-2.86 (m, 1H), 2.55-2.71 (m, 1H), 2.21-2.33 (m, 4H), 1.91-1.99 (m, 2H), 1.57-1.74 (m, 4H), 1.29-1.43 (m, 4H).
Reaction SMILES: P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+].[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.Cl.N[C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26]>CO>[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]1[S:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[N:15]=1
Reactant: N#Cc1ccc(O)cc1O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CSC(c2ccc(O)cc2O)=N1
Yield: 69.2 %

Procedure:
In a mixed solvent including methanol (30 mL) and phosphate buffer solution (20 mL), NaHCO3 (466 mg, 5.55 mmol) was carefully added to a solution including the obtained Compound 101a (0.5 g, 3.70 mmol) and L-cysteine hydrochloride monohydrate (974 mg, 5.55 mmol), and the reaction mixture was refluxed for 10 hours. After methanol was evaporated, the reaction mixture was acidified by using 1 N HCl to increase a pH to 2. The resultant precipitate was filtered, and washed with water to obtain Compound 101b (613 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[CH2:16][C:17](O)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([C:11]#[N:12])([CH3:10])[CH3:9].C1N=CN(C(N2C=NC=C2)=O)C=1.C([O-])(=O)[CH2:39][C:40]([O-])=[O:41]>C(C(C(OC(C)(C)C)=O)C(OC)=O)C.CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][C:17](=[O:18])[CH2:39][C:40](=[O:41])[O:20]2)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:10])([CH3:9])[C:11]#[N:12]
Reactant: O=C([O-])CC(=O)[O-]
Reactant: CC(C)(C#N)c1ccc(C=CC(O)(CC(=O)O)C2CCCC2)cc1Cl
Agent: CCC(C(=O)OC)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Temperature: 42 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
5-[3-Chloro-4-(cyano-dimethyl-methyl)-phenyl]-3-cyclopentyl-3-hydroxy-pent-4-enoic acid, from step 1 above, was dissolved in methyl tert-butyl ethylmalonate (3 mL). 4-DMAP (0.16 g, 0.13 mmol) and CDI (0.27 g, 1.68 mmol) were added and the reaction mixture was stirred under argon for 2 hours. In a separate flask was placed magnesium-bis-monoethyl malonate (0.74 g, 2.58 mmol) was suspended in THF (3 mL) and the mixture was heated to 42° C. The acylimidazole solution was added via cannula to the malonate mixture and the reaction was heated to 42° C. for 2 hours. The solvent was removed in vacuo to give a residue that was partitioned between 1N HCl and EtOAc. The organic layer was dried over MgSO4 and concentrated to a clear oil (0.56 g, 100%). The oil was dissolved in a 0.3 M NaOH solution in MeOH/H2O 1:1 (6 mL), and stirred overnight at room temperature. The reaction mixture was partitioned between H2O and IPE. The aqueous layer was made acidic with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give the product (0.45 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 1.39-1.71 (m, 8H), 1.81-1.87 (m, 8H), 2.10-2.15 (m, 1H), 2.59-2.68 (m, 2H), 3.51 (s, 2H), 3.75 (s, 2H), 7.11 (dd, J=8.1 Hz, 1.8), 7.27 (d, J=1.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H). ESIMS (MH+): 388.
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[N:6]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29]Cl)=[CH:26][CH:25]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>CC(CC)=O>[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29][N:19]2[CH2:20][CH2:21][N:16]([C:7]3[N:8]=[C:9]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:4]4[CH:3]=[C:2]([CH3:1])[S:22][C:5]=4[N:6]=3)[CH2:17][CH2:18]2)=[CH:26][CH:25]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: Cc1cc2c(-c3ccccc3)nc(N3CCNCC3)nc2s1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(-c3ccccc3)nc(N3CCN(CC(=O)c4ccc(F)cc4)CC3)nc2s1
Yield: 91.8 %

Procedure:
In 6 ml of methylethylketone, 2.03 g of 6-methyl-4-phenyl-2-piperazinyl-thieno[2,3-d]pyrimidine, 1.25 g of 4-fluorophenacyl chloride and 0.73 g of triethylamine are reacted under reflux for 5 hours. After cooling, 70 ml of chloroform is added to the reaction mixture. The solution is washed twice with 100 ml of water and then saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After distilling off chloroform, crystallization from diethylether/methanol gives 2.68 g of the product which has a melting point of 141°-142° C.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:38])([CH3:37])[CH2:10][CH2:11][C:12]1[C:17]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[CH:28]=[CH:27][N:26]3[N:29]=[CH:30][C:31]([C:32]([O:34]C)=O)=[C:25]3[N:24]=2)=[CH:16][C:15]([F:36])=[CH:14][N:13]=1)=O)(C)(C)C.[OH-].[Li+].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C1COCC1.CO.CN(C=O)C>[F:36][C:15]1[CH:16]=[C:17]2[C:12](=[N:13][CH:14]=1)[CH2:11][CH2:10][C:9]([CH3:37])([CH3:38])[NH:8][C:32](=[O:34])[C:31]1=[C:25]3[N:24]=[C:23]([CH:28]=[CH:27][N:26]3[N:29]=[CH:30]1)[N:19]1[C@@H:18]2[CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3CCC(C)(C)NC(=O)OC(C)(C)C)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C(=O)N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To (R)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3-methylbutyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (166 mg, 0.315 mmol) in THF/MeOH (3 mL/1 mL) was added lithium hydroxide (946 μL, 1.89 mmol). The reaction vessel was sealed and heated to 70° C. for 3 hours. The reaction mixture was then dried under reduced pressure and HCl (4 mL, 4M in dioxane) was added. The reaction mixture was stirred for one hour, then the solvent was removed and the residue was dried under high vacuum for two hours. To the residue was then added DMF (8 mL), HOBT-H2O (96.5 mg, 0.630 mmol), EDCI (121 mg, 0.630 mmol) and triethylamine (159 mg, 1.58 mmol). The reaction mixture was stirred at 45° C. for 18 hours, then concentrated under vacuum The residue was purified by silica column chromatography eluting with 5% MeOH/DCM to afford the title compound (60.0 mg, 48.3% yield). MS (apci) m/z=395.1 (M+H).
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(OC(C)(C)C)=O.[ClH:18].CCOCC>O1CCOCC1>[ClH:18].[CH3:1][NH:8][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
3-(N-Me,N-nPr Carbamyloxy) N-Boc,N-methyl phenethylamine (6.0 g, 17.14 mmol) was dissolved in dioxane (60 ml) and 20% HCl/ether (60 ml) was added. The mixture was stirred at RT for 4 hrs and evaporated to dryness in-vacuo, and the residual oil was treated with ether (2×150 ml), to give, after stirring and ice-cooling, 4.6 g (93.5%) of the title compound as a white solid. In this manner the compounds shown in Table 2 were prepared, their analytical characteristics are given in Table 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C@@H:13]([OH:17])[C:14]([OH:16])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:21][C@H:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][C:26]([OH:32])=[CH:27][CH:28]=2)[CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:13]([OH:17])[C:14]([NH:21][C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][C:26]([OH:32])=[CH:27][CH:28]=3)[CH2:23]2)=[O:16])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Reactant: O=C(O)[C@H](O)c1ccc(OCc2ccccc2)cc1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccc(OCc2ccccc2)cc1
Yield: 91.7 %

Procedure:
(R)-4-Benzyloxymandelic acid (2.43 g), (S)-2-amino-7-hydroxytetralin hydrobromide (2.87 g) and triethylamine (2.88 ml) were dissolved in dichloromethane (38 ml), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.58 g) was added to the solution at room temperature with stirring. After reaction for 15 hours, ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine successively, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: chloroform/ethyl acetate=1/1) and following recrystallization from ethyl acetate-hexane gave (2R)-2-(4-benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (3.48 g) having a melting point of 137-139° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([CH2:15][CH3:16])[C:13]#[N:14].[CH2:17](N)[CH2:18][NH2:19]>>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([C:13]1[NH:19][CH2:18][CH2:17][N:14]=1)[CH2:15][CH3:16]
Reactant: CCC(C#N)c1cccc(C(F)(F)F)c1F
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cccc(C(F)(F)F)c1F

Procedure:
rac-2-[1-(2-Fluoro-3-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-fluoro-3-trifluoromethyl-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b): colourless powder; MS (ISP): 275.0 ((M+H)+.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1)=[N+:2]=[N-:3].[OH-].C[Sn+](C)C>ClCCCl>[N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C@H:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([OH:17])=[O:16])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H](Cc1ccc(OCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)O
Temperature: 80 °C
Yield: 69.9 %

Procedure:
A solution of 2A (1.46 g, 4.0 mmol) was dissolved in 1,2-dichloroethane (20 mL) and after addition of trimethyltin hydroxide (2.17 g, 12.0 mmol), the mixture was heated at 80° C. until TLC analysis indicated a complete reaction. After completion of the reaction, the mixture was concentrated in vacuo, and the residue was taken up in EtOAc (80 mL). The organic layer was washed with aqueous HCl (5%) (3×50 mL). The organic layer was then washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by flash column chromatography (SiO2, step-wise gradient from 2-20% MeOH in CH2Cl2) to give 3A (0.98 g, 70%) as a white solid. 1H NMR (600 MHz, CDCl3): δ 7.11 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=8.4 Hz), 4.94 (1H, d, J=7.2 Hz), 4.53-4.60 (1H, m), 4.13 (2H, t, J=5.4 Hz), 3.58 (2H, t, J=5.4 Hz), 3.14 (1H, dd, J=13.8, 5.4 Hz), 3.04 (1H, dd, J=13.8, 5.4 Hz), 1.43 (9H, s); 13C NMR (150 MHz, CDCl3): δ 157.3, 155.5, 130.5, 128.8, 114.7, 80.2, 66.9, 54.7, 50.1, 37.0, 28.3; MS (ESI, m/z): 373 (M+Na)+.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.B(F)(F)F>C(OCC)C.C(Cl)Cl>[CH3:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a 250 ml. 3-necked round bottom flask equipped with a thermometer, stirrer, condenser and dropping funnel were added 10.88 g. (40 mmole) of 7-aminocephalosporanic acid and 70.5 ml. of trifluoroacetic acid. Triethylsilane (17.2 g., 150 mmole, 23.6 ml.) was added to the solution followed by 33.6 ml. of methylene chloride. The resulting solution was stirred at room temperature and 27.1 g. (190.7 mmole, 23.6 ml.) of boron trifluoride etherate were added. The temperature of the reaction mixture rose to about 55° C. following the addition of the boron trifluoride. After the temperature of the mixture had cooled to room temperature, the mixture was poured with stirring into 250 ml. of diethyl ether. The precipitate of the trifluoroacetate salt of 7-aminodesacetoxycephalosporanic acid was separated by filtration and was dissolved in 100 ml. of water containing 50 ml. of acetone. The pH of the orange-colored solution was adjusted to 4.0 with ammonium hydroxide to precipitate 7-ADCA in the zwitterionic form. The product was separated by filtration and was washed with aqueous acetone, acetone, and then with diethyl ether and was dried. There were obtained 7.23 g. (84.5% yield) of 7-ADCA as a fine off-white powder.