Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:10][CH2:11][N:12]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C2(CCO)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Solvent: ClCCl
Product: Cc1cccc(C2(CCOS(C)(=O)=O)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C

Procedure:
3.8 ml of methanesulfonyl chloride are added dropwise to 21 g of 4-(2-hydroxyethyl)-4-(3-methyl-phenyl)-N-tritylpiperidine (prepared according to scheme 5) dissolved in 200 ml of methylene chloride, cooled to 0° C. The reaction mixture is left for half an hour at room temperature, washed twice with water, dried over MgSO4 and concentrated under vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19]C=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].C1(CN2CCN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)CCC1>>[CH:22]1([CH2:17][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CCC3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)O
Yield: 77 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(cyclobutylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 77% yield: MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[OH-].[K+].[N:12](OCCC(C)C)=[O:13]>C(O)C>[CH3:1][C:2]1[C:8]([OH:9])=[C:7]([N:12]=[O:13])[CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: CC(C)CCON=O
Reactant: Cc1c(O)cccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(O)ccc(N=O)c1O
Reaction time: 3 h

Procedure:
19.8 g. 2-Methylresorcinol and 13.4 g. potassium hydroxide are dissolved in 120 ml. ethanol and cooled to 5° C. 24 ml. Isopentyl nitrite are added dropwise thereto, the reaction mixture is stirred for 3 hours and the precipitate is filtered off with suction. The yellow solid material is stirred into 200 ml. 5N sulphuric acid, the bright yellow product thereby precipitating out. Yield 22 g.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C(C(O)=O)=[CH:9]1.CN(C=O)C>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Oxalyl chloride (1.10 ml, 12.5 mmol) was added to a solution of 1-methylindole-3-carboxylic acid (2.00 g, 11.4 mmol) and DMF (0.18 ml, 2.28 mmol) in methylene chloride (25 ml) and the resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent to give 1-methylindole-3-carboxylic acid chloride (2.19 g, 99%) as a pale yellow solid. The resulting 1-methylindole-3-carboxylic acid chloride (752 mg, 3.88 mmol) was added in portions to a solution of ethyl 3-amino-2-chloro-6-pyridylacetate (833 mg, 3.88 mmol) and triethylamine (1.08 ml, 7.77 mmol) in methylene chloride (20 ml) under stirring at 0° C. The reaction mixture was heated under reflux for 8 hours. After cooling to room temperature and addition of water, the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (2:1, v/v) eluate fractions, ethyl 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetate (859 mg, 60%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO[2H]>[NH2:1][CH:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:13][OH:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [2H]OC
Product: NC(CO)Cc1c[nH]c2ccccc12
Yield: 92 %

Procedure:
The title compound was prepared from tryptophan according to Method D and was isolated as a solid in 92% yield. δH (MeOD-d3) 7.46 (1H, d, J 7.9 Hz), 7.21 (1H, d, J 8.0 Hz), 6.96 (3H, m), 3.79 (1H, dd, J 11.3 and 3.6 Hz), 3.54 (1H, dd, J 11.2 and 6.2 Hz), 3.05 (1H, m), 2.80 (1H, m), 2.61 (1H, m). Note: exchangeable protons not evident in MeOD.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5]2.[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=2)[N:28]=1.C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>O1CCOCC1.[Cu](I)I>[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=2)[N:28]=1.[CH2:35]([O:34][C:32]([C:30]1[N:31]=[C:26]2[CH:25]=[CH:24][C:23]([NH:21][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])=[N:28][N:27]2[CH:29]=1)=[O:33])[CH3:36]
Reactant: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: I[Cu]I
Agent: CCOC(=O)c1cn2nc(Br)ccc2n1
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2nc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 5.5 %

Procedure:
Compound 21 was prepared according to a process similar to that described in Example 20, by reacting 0.4 g (1.40 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, with 0.41 g (1.54 mmol) of ethyl 6-bromoimidazo[1,2-b]pyridazine-2-carboxylate, prepared according to the protocol described in step 21.1, in the presence of 80 mg (0.42 mmol) of copper iodide, 0.38 g (2.79 mmol) of potassium carbonate and 53 mg (0.46 mmol) of trans-1,2-cyclohexanediamine in 10 mL of dioxane. 20 mg of the expected product are thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[C:14]([C:18]1[CH:19]=[C:20]2[C:25](=O)[O:24][C:22](=[O:23])[C:21]2=[CH:27][CH:28]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[C:20]2[C:21](=[CH:27][CH:28]=1)[C:22](=[O:23])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:25]2=[O:24])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Product: COC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.14 g, 14%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 4-t-butylphthalic anhydride (0.70 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:11]=[C:9](/[CH:8]=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:10][CH:16]=1
Reactant: NC(=O)C=CC1CCCCC1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(/C=C/C2CCCCC2)n1
Yield: 4.5 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-cyclohexylpropeneamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-[(E)-2-cyclohexylethenyl]oxazole. The yield was 4.5%. Oily substance.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][C:3]1[C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:8]
Reactant: Cc1c(Br)ccc[n+]1[O-]
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1c(N2CCNCC2)ccc[n+]1[O-]
Temperature: 90 °C
Yield: 43 %

Procedure:
3-Bromo-2-methyl-pyridine 1-oxide (a total of 388 mg, 2.06 mmol), sodium tert-butoxide (a total of 392 mg, 4.08 mmol), piperazine (a total of 651 mg, 7.56 mmol) and RuPhos (a total of 58 mg, 0.12 mmol) were divided in three batches and dissolved in anhydrous dioxane (total volume of 15 ml), and purged with argon for 5 minutes. A total of Pd2(DBA)3 (60 mg, 0.064 mmol) was added and each batch was heated in a closed vial for 22 hours at 90° C. The combined reaction mixtures were filtered through kieselguhr and concentrated under reduced pressure to give a brown oil that was purified by column chromatography (silica, gradient from 0 to 10% of methanol containing 7N ammonia in DCM) to give 170 mg (0.88 mmol, yield 43%) MS (multi-mode) m/z=194.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([OH:20])[C:9](=[O:28])[C:8]=3[CH:7]=[CH:6][N:5]2[C:29]=1[CH3:30].[BH4-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@:10]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([OH:20])[C@@H:9]([OH:28])[C:8]=3[CH:7]=[CH:6][N:5]2[C:29]=1[CH3:30]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@](O)(Cc1ccccc1)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)[C@H](O)[C@](O)(Cc1ccccc1)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.3 %

Procedure:
A mixture of 0.8 g of (8S,9R)-2,3-dimethyl-8-benzyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]naphthyridin-7-one suspended in 20 ml of methanol is treated in portions with 3.3 g of sodium borohydride (30 minutes), stirred at room temperature for 20 h and then refluxed for 5 h. It is then concentrated to dryness in vacuo and stirred into a mixture of 20 ml of water and 20 ml of dichloromethane, the mixture is adjusted to pH 8 using dilute hydrochloric acid with cooling, after separating off the aqueous phase this is extracted a further three times with 50 ml of dichloromethane each time, and the organic phases are combined, washed with a little water and concentrated to dryness in vacuo on a rotary evaporator. The residue obtained is purified on silica gel (eluent: dichloromethane/methanol 13/1). 0.3 g of the title compound of melting point 115-22° C. (diisopropyl ether) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:39]([O:40][CH2:41][CH:42]([F:44])[F:43])=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28]C(OC(C)(C)C)=O)[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:39]([O:40][CH2:41][CH:42]([F:43])[F:44])=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH2:28])[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21
Reaction time: 2 h

Procedure:
A mixture of N-(3-chloro-4-fluoro-phenyl)-2-{2,6-dichloro-3-[(tert-butoxy-carbonylamino)-methyl]phenylamino}-6-(2,2-difluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (4.0 g, 5.9 mmol, prepared in analogy to example 75 from N-(3-chloro-4-fluorophenyl)-2-(2,2-difluoroethoxy)-4-methylamino-5-amino-benzamide with building block B), 4 M HCl in dioxane (50 mL) and dioxane (200 mL) is stirred for 2 h. The precipitate is filtered off, washed with water and diluted with 10 mL conc. aq. NH3. The mixture is extracted with EtOAc, the organic phase is dried with Na2SO4 and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([C:22]2[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=2)([N+:20]#[C-])[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:36][CH:37]([CH3:39])[CH3:38].Cl>CO.O1CCOCC1>[NH2:20][C@:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:36][CH:37]([CH3:39])[CH3:38])[CH:4]=1)([C:22]1[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: [C-]#[N+][C@@](Cc1ccc(C(=O)OC)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C[C@](N)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC(C)C)c2)cc1
Reaction time: 0.05 h
Yield: 86.5 %

Procedure:
To a solution of (R)-methyl 4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate (120 mg, 0.22 mmol) in MeOH (2 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction mixture was stirred for 3 minutes. The reaction solvent was evaporated under a stream of nitrogen. The residue was diluted with EtOAc (15 mL), washed with saturated sodium bicarbonate solution (10 mL) and sat. NaCl, dried over MgSO4, filtered and evaporated to yield (R)-methyl 4-(2-amino-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate (103 mg, 86% yield) as a clear glass. LCMS: RT=1.87 min [M−NH2] 525.1 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm).
Reaction SMILES: B(O)O.O[C:5](C(O)(C)C)([CH3:7])[CH3:6].C(B1OC(C)(C)C(C)(C)O1)C=C.[CH:24]([C:26]1[C@H:31]([C:32]([O:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[N:30]2[C:48](=[O:60])[C@@H:49]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@H:29]2[S:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1>[OH:25][CH:24]([C:26]1[C@H:31]([C:32]([O:34][CH:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:33])[N:30]2[C:48](=[O:60])[C@@H:49]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C@H:29]2[S:28][CH:27]=1)[CH2:7][CH:5]=[CH2:6]
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: C=CCB1OC(C)(C)C(C)(C)O1
Agent: OBO
Solvent: Cc1ccccc1
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
via a pinacol boronate. A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.3 mmol), diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol), 0.4 nm molecular sieves (50 mg), and toluene (2 ml) was heated under reflux for 3 h and then cooled and purified by chromatography as in part a to give the title compound S-diastereomer, 20 mg (18%), and the R-diastereomer, 23 mg (20%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+].[N:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[C:16](C(O)=O)[CH:15]=1>O>[Br:1][C:16]1[CH:15]=[N:14][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: O=C(O)c1cnn2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1cnn2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
N-Bromosuccinimide (3.06 g, 17.22 mmol) and sodium hydrogen carbonate (4.34 g, 51.66 mmol) were added to a solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid (Preparation 22b, 2.81 g, 17.22 mmol) in NN-dimethylformamide (40 mL) and the resulting mixture was stirred at room temperature for 4 h before being poured over 100 mL of water. The resulting suspension was extracted twice with ethyl acetate and the combined organic layers were dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (8:2 hexane/ethyl acetate) to yield the title compound (2.58 g, 76%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[OH-].[Na+]>C(O)C>[OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1cc(C(O)C(C)C)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(O)c1cc(C(=O)O)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 159.1 %

Procedure:
Ethyl 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylate (2.345 mmol, 0.5 g) was dissolved in ethanol (5 ml) and cooled to 0° C. NaOH 1 M solution (5 ml) was slowly added and the resulting mixture was allowed to warm to RT. The solution was heated to 60° C. for 3 h. Ethanol was removed by evaporation and the residue was diluted with tert-butyl methyl ether. The mixture was cooled to 0° C. and acidified with 2 N HCl solution. The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was extracted with DCM. Both organic and aqueous phases contained the product so both they were combined and evaporated. 0.691 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 0.85 (d, 3H), 0.91 (d, 3H), 2.03 (qd, 1H), 4.54 (d, 1H), 6.66 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([OH:19])=[O:18])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:23])(=O)=O>COP(OC)(OC)=O.O>[Cl:23][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]2[O:11][CH:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]([OH:19])=[O:18])=[CH:8][C:7]=2[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cccc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Solvent: COP(=O)(OC)OC
Solvent: O
Product: CCc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 117.4 %

Procedure:
8-Ethyl-2-(trifluoromethyl)2H-1-benzopyran-3-carboxylic acid (Example 28) (0.68 g, 2.5 mmol) was dissolved in trimethylphosphate (5 mL) and was treated with sulfuryl chloride (0.35 g, 2.62 mmol) at 0° C. After stirring at 0° C. for 45 minutes and 1 hour at room temperature, the reaction was diluted with cold water (15 mL). The resulting oily mixture was extracted with hexanes-ethyl acetate. The organic phase was washed with brine, dried, and concentrated in vacuo yielding the title compound as a solid (0.9 g, 117%): mp 197.2–199.1° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J=2.7 Hz), 7.30 (d, 1H, J=2.4 Hz), 5.88 (q, 1H, J=7.2 Hz), 2.65 (m, 2H), 1.19 (t, 3H, J=7.5 Hz). FABLRMS m/z 307 (M+H). Anal. Calc'd for C13H10ClF3O3: C, 50.92; H, 3.29. Found: C, 51.00; H, 3.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:6][CH:7]([CH:10]=[O:11])[CH:8]=[O:9].C(O)(=O)C.[CH:21]([NH2:23])=[NH:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:6][C:7]1[C:8]([OH:9])=[N:22][CH:21]=[N:23][C:10]=1[OH:11]
Reactant: COc1ccc(OC(C=O)C=O)cc1OC
Reactant: N=CN
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(O)ncnc2O)cc1OC

Procedure:
By condensing 2-(3,4-dimethoxy-phenoxy)-propane-1,3-dione acid with formamidine acetate there was obtained 5-(3,4-dimethoxyphenoxy)-pyrimidine-4,6-diol, therefrom with POCl3 there was obtained 4,6-dichloro-5-(3,4-dimethoxy-phenoxy)-pyrimidine, therefrom with p-tert-butylbenzenesulfonamide K there was obtained 4-tert-butyl-N-[6-chloro-5-(3,4-dimethoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide and therefrom with Na ethylene glycolate there was obtained p-tert-butyl-N-[5-(3,4-dimethoxy-phenoxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CN(C)CCCl
Reactant: COc1ccccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1NCCN(C)C
Temperature: 25 °C
Yield: 48.2 %

Procedure:
2-Anisidine (5.9 ml, 0.05 mole) and 2-dimethylaminoethyl chloride hydrochloride (5.0 g, 0.035 mole) were dissolved in ethanol (75 ml) and treated with sodium carbonate (7.42 g, 0.07 mole). The mixture was heated under reflux for 7 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate evaporated in vacuo. The residue was dissolved in H2O and 10% NaOH solution was added until basic. The mixture was extracted into Et2O, dried (Na2SO4) and evaporated in vacuo to give an orange oil. This was purified by flash column chromatography, eluting with ethyl acetate to afford the title compound as a pale orange oil (3.28 g, 48%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].F[C:8]1[CH:9]=[C:10]([CH3:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].C(=O)(O)[O-].[Na+]>CO>[CH3:17][C:10]1[CH:9]=[CH:8][C:13]([N+:14]([O-:16])=[O:15])=[C:12]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:11]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CSc1cc(C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.9 %

Procedure:
Methyl thioglycolate (3.18 g) was added to a mixture of 3-fluoro-4-nitrotoluene (4.65 g), sodium bicarbonate (3 g) and methanol (46 ml) and the mixture was heated to 70° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of diethyl ether and hexane to give methyl 2-(5-methyl-2-nitrophenylthio)acetate (6.5 g, 90%), m.p. 74°-75° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[S:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([O:10][CH3:11])=[O:9].CN1CCOCC1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH:21]=[C:22]=[CH2:23]>C(Cl)Cl>[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]2[CH2:5][CH2:6][S:7][C:2]([CH3:12])([CH3:1])[C@@H:3]2[C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH:21]=[C:22]=[CH2:23]
Reactant: COC(=O)[C@@H]1NCCSC1(C)C
Reactant: C=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a solution of product from Example 23 (155 mg, 0.82 mmol) in methylene chloride (5 ml) was added N-methylmorpholine (0.180 ml, 1.64 mmol) followed by the product from Example 5 (200 mg, 0.82 mmol). The resulting mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. The crude residue was purified by flash chromatography to give 170 mg (52%) of the product.