Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14]/C=C/C)[C@@H:12]([O:18]/C=C/C)[C@H:11]([O:22]/C=C/C)[C@@H:10]([CH2:26][O:27]/C=C/C)[N:9]2[CH3:31])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1>C1COCC1.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:18])[C@H:11]([OH:22])[C@@H:10]([CH2:26][OH:27])[N:9]2[CH3:31])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=1
Reactant: C/C=C/OC[C@@H]1[C@@H](O/C=C/C)[C@H](O/C=C/C)[C@@H](O/C=C/C)[C@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)N1C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)N3C)ccc2Cl)cc1
Temperature: 70 °C
Yield: 55.9 %

Procedure:
Compound from Step B (54 mg, 0.093 mmol) was dissolved in a solution of THF/AcOH/1NHCl (0.5 ml:0.6 ml:0.30 ml) and heated to 70° C. for 30 minutes. The mixture was concentrated to give a pale yellow oil. Purification by preparative HPLC (sunfire C18, 30×100 mm, 5 μm, 10%-100% B over 15 minutes) afforded (2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol (22 mg, 0.052 mmol, 56%) as a white solid. MS (ES+) [M+H]+=422.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][S:31](=[O:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][S:31](=[O:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCS(=O)CC2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCS(=O)CC2)C1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[(1-oxidothiomorpholin-4-yl)carbonyl]piperidine-1-carboxylate (120 mg) was dissolved in chloroform (3 ml), TFA (1 ml) was added and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (100 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(=S)=S>[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:1](=[O:3])[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(C)=O)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A round-bottomed flask was charged acetyl chloride (4.20 g, 53.56 mmol, 1 eq), AlCl3 (7.13 g, 53.56 mmol, 1 eq), and carbon disulfide (80 mL). To the mixture was added dropwise a solution of 3-bromoanisole (9.75 g, 52.13 mmol) in carbon disulfide (20 mL) and stirred for 16 h. The resulting solution was diluted with ice water (100 mL) and extracted with CH2Cl2 (50 mL×3). The extracts were washed with H2O, brine, and 1N NaOH (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:10) to afford the title compound (6.2 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH:22]([C:27](OCC)=[O:28])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2[C:6]3[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:11][C:27](=[O:28])[C:22]=2[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: COc1ccc(O)cc1OC
Agent: Cl
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(Cc1ccccc1)C3
Yield: 40 %

Procedure:
Prepared by the procedure of Example 1 from 3,4-dimethoxyphenol and ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride. Yield 40%; mp 189°-191° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][N:3]=[N:2]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1([CH2:6][C:7]([Cl:13])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1cnnn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)Cn1cnnn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(1H-tetrazol-1-yl)acetic acid 3 (1 gm, 7.81 mmol) in benzene (20 mL) was added oxalyl chloride (1.5 g, 11.81 mmol) and a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under vacuum and the crude acid chloride 4 obtained was used for the next step without any purification.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([O:7]C)=[O:6])[CH3:3].[OH-].[Na+]>>[OH:1][CH:2]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([OH:7])=[O:6])[CH3:3]
Reactant: C=CCCCC(C(=O)OC)C(C)O
Agent: [Na+]
Agent: [OH-]
Product: C=CCCCC(C(=O)O)C(C)O

Procedure:
Analogously to Example 15A, 4.80 g (25.8 mmol) of methyl 2-(1-hydroxyethyl)-6-heptenoate (Example 21A) are reacted with 39.0 ml of a 1 M sodium hydroxide solution to give 2-(1-hydroxyethyl)-6-heptenoic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[Cl:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:16][CH2:17][CH2:18][NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCl
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Using the general method of Example 1 Part A, 4-chloro-3-nitroquinoline (15.0 g, 71.90 mol) was reacted with 2-chloroethylamine monohydrochloride (8.3 g, 71.90 mmol). The crude product was suspended in water (300 mL) and solid sodium carbonate was added to adjust the pH to 10. The suspension was stirred overnight and then cooled in an ice bath. The solid was then isolated by filtration and washed with chilled water to provide 15.88 g of N-(2chloroethyl)-3-nitroquinolin-4-amine as a bright yellow fluffy solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>CCO.C1COCC1.O.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[O:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[N:15][CH:14]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1)C(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Temperature: 80 °C
Yield: 86 %

Procedure:
Methyl 3-methyl-2-(5-(4-nitrophenyl)oxazole-2-carboxamido)butanoate (step E product, 700 mg) was dissolved in a solvent mixture of EtOH (7 ml), THF (2.8 ml), and water (2.8 ml). Ammonium chloride (323 mg) and iron (264 mg) were then added and the reaction mixture was refluxed at 80° C. for 3 hours. It was then cooled, filtered through celite and the solvent was removed under reduced pressure to get dark brown residue. The residue was dissolved in water and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated to get dark brown residue which was purified by silica gel column chromatography in 2.5:7.5 EtOAc:CHCl3 to get yellow solid which was crystallized in DCM/Pet ether to yield 550 mg (86%) yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 8.83 (d, 1H), 7.55 (s, 1H), 7.48 (d, 2H), 6.66 (d, 2H), 5.63 (bs, 2H), 4.28 (m, 1H), 3.67 (s, 3H), 1.98 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH2:18])[CH2:8]1.O1CCOCC1>O>[NH2:18][CH:9]1[CH:8]=[CH:7][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10]1
Reactant: NC1CCc2ccccc2C(O)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: NC1C=Cc2ccccc2CC1
Temperature: 20 °C
Yield: 59.6 %

Procedure:
12 ml of 18N sulfuric acid were added to a refluxing mixture of 5.6 g of the product of Step C and 60 ml of dioxane and the mixture was refluxed for 2 hours and then was cooled to 20° C. The mixture was poured into 300 ml of water and the neutral fraction was extracted with ether. The aqueous phase was made alkaline with sodium hydroxide addition and was extracted with ethyl acetate. The ethyl acetate extracts were washed with aqueous sodium chloride solution, dried, filtered and evaporated to dryness to obtain 5 g of raw product. The latter was chromatographed over silica gel and was eluted with an 8-2-1 ethyl acetate-benzene-triethylamine mixture to obtain 3 g of 7-amino-6,7-dihydro [5H] benzocycloheptene in the form of a brown oil.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1>C(Cl)Cl.N1C=CC=CC=1.CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(c4cccnc4)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (100 mg, 0.21 mmol), 3-pyridineboronic acid (265 mg, 2.10 mmol), Cu(OAc)2 powder (190 mg, 1.05 mmol) in 5 mL DCM and 1 mL pyridine was stirred at RT for 2 days. It was diluted with methanol and filtered through celite. The filtrate was treated with TFA and concentrated in vacuo. The residue was subjected to reverse phase HPLC to isolate the title compound. MS found for C29H28F2N6O as (M+H)+ 515.5. UV: λ=268 nm. 1H NMR: (CD3OD) δ 8.41 (1H, m), 8.16 (1H, s), 8.09 (1H, s), 8.06 (1H, s), 7.81 (1H, m), 7.35 (2H, dt, J=8.4; 2.0 Hz), 7.24 (1H, m), 7.16 (1H, m), 7.12-7.07 (3H, m), 5.79 (1H, s), 4.55 (2H, s), 4.12 (2H, m), 3.13 (2H, m), 2.91 (1H, m), 2.04 (2H, m), 1.87 (2H, m) ppm.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]2)=[C:8]([Cl:18])[CH:7]=1)[CH3:5].[OH-].[K+].O>C(O)C>[Cl:18][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:19])=[O:2])[CH:11]=[CH:10][C:9]=1[N:12]1[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]1
Reactant: COC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 94.7 %

Procedure:
3.0 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid methyl ester, 1.4 g of potassium hydroxide, 1.5 ml of water and 20 ml of ethanol are heated to the boil for 2 hours, the alcohol is distilled off, water is added and extraction with benzene is effected. This is followed by clarification of the aqueous phase with activated charcoal and acification with 2 N hydrochloric acid to produce 2.7 g (95% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)-phenyl]propionic acid (m.p. 102° to 103° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3]1)=[C:11]1[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][S:15][C:10]1=[CH:9][CH:8]=3.[H-].[Na+].[CH2:26](Br)[CH2:27][CH3:28]>>[CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[N:6]([CH2:26][CH2:27][CH3:28])[C:7]3[C:12]([C:4]=2[CH2:3]1)=[C:11]1[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][S:15][C:10]1=[CH:9][CH:8]=3
Reactant: CCCBr
Reactant: CN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1
Agent: [H-]
Agent: [Na+]
Product: CCCn1c2c(c3c4c(-c5ccccc5)csc4ccc31)CN(C)CC2

Procedure:
The compound is formed analogously to that described in Example 28, from 4.8 g of 9-methyl-1-phenyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, NaH and 1.5 ml of propyl bromide. Melting point: 156° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1.[CH2:26](Br)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:26]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NC1CCNCC1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NC1CCN(CCc2ccccc2)CC1

Procedure:
In 10 ml of ethanol was suspended 0.998 g (2.5 mM) of N-(piperidin-4-yl)-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide dihydrochloride as well as 0.703 g (3.8 mM) of phenethyl bromide, followed by addition of 1.74 ml (12.5 mM) of triethylamine, and the mixture was refluxed for 5 hours. To this reaction mixture was further added 0.070 g (0.38 mM) of phenethyl bromide, and the mixture was refluxed overnight. This reaction mixture was diluted with 5% aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol=4/1) and concentrated and the residue was crystallized from ether to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].I[CH3:35].O>CN(C=O)C>[CH3:35][N:19]([C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[N:18]=1
Reactant: CI
Reactant: COc1ccccc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1nc(-c2ccccc2O)nc2ccccc12)[C@H]1CCNC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
(S)-tert-Butyl 3-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.259 g, 0.616 mmol) (prepared by methods analogous to those described in Synthesis 2) was dissolved in DMF (6.16 mL) and cooled to −30° C. NaH (60% dispersion in mineral oil, 0.041 mg, 0.678 mmol) was added and the mixture was stirred at −30° C. for 15 minutes. The mixture was cooled to −78° C. and iodomethane (0.046 mL, 0.727 mmol) was added dropwise. The solution was warmed to room temperature over 2 hours. Water (5 mL) was added and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (1.3 mL) and 1 M boron tribromide in dichloromethane (1.3 mL). The solution was stirred at room temperature for 18 hours. Methanol (5 mL) was added and the mixture was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with a gradient from 3% to 30% methanol in dichloromethane, gave the title compound as a yellow solid (0.028 g, 66%).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][C:20]([NH:22][CH3:23])=O)[CH:16]=2)[NH:11][N:10]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][NH:22][CH3:23])[CH:16]=2)[NH:11][N:10]=1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]nc(C)c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Agent: O=C([O-])C(F)(F)F
Product: CNCCC(c1ccccc1)c1ccc2[nH]nc(C)c2c1

Procedure:
[3-(3-Methyl-1H-indazol-5-yl)-3-phenyl-propyl]-methyl-amine CCXXII was prepared as a trifluoroacetate from 3-(3-methyl-1H-indazol-5-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=280.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.S1(CCCC1)(=O)=O.C[C:22]([O:24][CH2:25][C:26]1[CH2:35][S:34][C@@H:29]2[C@H:30]([NH2:33])[C:31](=[O:32])[N:28]2[C:27]=1[C:36]([OH:38])=[O:37])=O.N>>[NH2:33][CH:30]1[C:31](=[O:32])[N:28]2[C:27]([C:36]([OH:38])=[O:37])=[C:26]([CH2:25][O:24][CH3:22])[CH2:35][S:34][C@H:29]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Agent: N
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 115.5 %

Procedure:
8.94 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2) and 2.10 g of trimethyl borate were added to 15 ml of sulfolane. The mixture was cooled to 20° C. 2.74 g of 7-ACA were added to the mixture and the mixture was stirred for 1.5 hours at 20° C. The progress of the reaction was examined by high performance liquid chromatography (HPLC). After completion of the reaction, the reaction mixture was poured over crushed ice and the pH was adjusted to 3.5 by addition of aqueous ammonia. The crystals precipitated were filtered off, washed with water and dried to afford 2.84 g of crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. After this, the crude crystals were dissolved in aqueous ammonia in order to adjust the pH to 7. This solution was then applied to an adsorption column (polystyrene type high porous polymer) and the pH of the effluent was adjusted to 3.5 using hydrochloric acid. The crystals precipitated were filtered off, washed with water and dried to give 2.14 g (yield 87%) of the title compound at a high purity.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:5]([O:4][CH2:3][CH2:2][Br:1])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
Treat 2-bromoethanol (107 g) in CH2Cl2 (2 L) at 0° C. with t-butyidimethylsilylchloride (143 g), NEt3 (130 g) and DMAP (11 g), allow the reaction mixture to warm to 23° C. and stir for 18 h. Wash the mixture with H2O (250 mL), 20% HCl (250 mL), 20% NH4OH (250 mL), dry (MgSO4) and concentrate to give 2-(t-butyidimethylsilyloxy)-ethylbromide (197 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:18])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C(O)C>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH:8]([CH3:18])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[O:10])[CH2:30][CH2:31]2)=[CH:32][CH:33]=1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CC2CCN(C(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Reaction time: 48 h
Yield: 100.2 %

Procedure:
2.80 g (0.02 mol) of potassium carbonate are added to a solution of 5 g (0.02 mol) of 2-bromo-4'-chloropropiophenone and 4.15 g (0.02 mol) of 4-(4-methoxybenzyl)-piperidine in 60 ml of dry ethanol and the mixture is heated under reflux for 5 hours, with stirring, and then left to stand for 48 hours. It is left to cool and filtered, the filter cake being washed with alcohol, and the filtrate is evaporated. An orange oily residue remains, which is taken up in a mixture of water and diethyl ether. The organic phase is separated off and the aqueous phase is extracted a second time with diethyl ether. The organic phases are combined, dried and evaporated to give 7.45 g of an orange-yellow oily residue, which crystallises partially at ambient temperature and which is used as such in the subsequent reduction.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:19]([Mg]Br)[CH2:20][CH2:21][CH3:22]>C1COCC1>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: CCCC[Mg]Br
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Solvent: C1CCOC1
Product: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 4-(5-trifluoromethyl-pyridin-2-yl)-benzaldehyde (1.0 g, 3.98 mmol) in andhydrous tetrahydrifuran (THF) (25 mL) that had been cooled to 0° C. in an ice bath is added n-butyl magnesium bromide (8.0 mL, 16.0 mmol) dropwise with stirring under nitrogen. The mixture is allowed to warm slowly to room temperature. The reaction is monitored by HPLC, and upon complete consumption of the aldehyde, quenched with 1N HCl. The mixture is diluted with ethyl ether and water, then extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The title compound is obtained after column chromatography (1.10 g or 3.20 mmol) at 80% yield.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([O:37][CH2:38][CH3:39])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:36])C.[Li+].[OH-]>>[CH:31]1([CH:14]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:37][CH2:38][CH3:39])[C:4]([OH:40])=[O:3])=[C:8]([CH3:36])[CH:9]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CCCC2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CCCC2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 3-(4-{cyclopentyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 3-(4-{cyclopentyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as a mixture of two diastereomeric racemates as colorless liquid.