Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[I:19])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[I:19][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[N:14]([CH3:18])[N:13]=1
Reactant: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(I)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.7 %

Procedure:
To a solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1-methyl-1H-indazole (1 g, 2.57 mmol) in THF (5 mL) was added TBAF (6.42 mL, 12.85 mmol) at 0° C., after the addition, the reaction mixture was warmed to room temperature and stirred for 0.5 hour, then H2O (25 mL) was added to the mixture and product extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was triturated with petroleum ether (5 mL), filtered and dried to give 3-iodo-1-methyl-1H-indazol-5-ol (0.85 g, 93.3%) as a white solid. Crude material used into the next step without further purification. LCMS: (M+H)+=275.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>>[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=3)=[O:10])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
A solution of 4-chloro-3-(trifluoromethyl)phenylisocyanate (14.60 g, 65.90 mmol) in CH2C12 (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (MethodA2, Step 4; 16.0 g, 65.77 mmol) in CH2C12 (35 mL) at 0° C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2C12 (2×30 mL) and dried under reduced pressure to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) as an off white solid (28.5 g, 93%)
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>C(O)(C)C>[OH:23][CH:20]([CH2:21][OH:22])[CH2:19][NH:18][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1nccnc1Cl
Reactant: NCC(O)CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1nccnc1NCC(O)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g (0.0094 mol) 3 and 1.01 g (0.01 mol) triethylamine in 25 ml isopropanol is added 0.91 g (0.01 mol) 3-amino-1,2-propanediol (10). The reaction mixture becomes reddish and is stirred at room temperature for 16 hours. The solvent is then removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel to afford pure 11 as a yellow solid, m.p. 100°-102°.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.Cl.[C:19]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:19]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2[nH]1
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a mixture of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (175 mg, 0.754 mmol) and 1-naphthalen-1-yl-piperazine hydrochloride (206 mg, 0.829 mmol) in DCE (4 mL) was added Et3N (0.23 mL, 1.66 mmol). The mixture was stirred for 10 min and NaBH(OAc)3 (224 mg, 1.06 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give a white foam. Purification by liquid chromatography (5% MeOH/CH2Cl2) gave the title compound as a white foam (260 mg, 0.607 mmol, 80%). The foam was dissolved in a minimal amount of CH2Cl2 and Et2O was added. 1M HCl in Et2O (0.6 mL) was added and a white precipitate formed. The solid was collected by filtration, washed with Et2O and dried to give a white fluffy solid (257 mg). MS: APCI: M+1: 429.2 (Exact Mass: 428.22).
Reaction SMILES: [CH2:1]([S:15][CH2:16][C:17](O)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[CH2:1]([S:15][CH2:16][CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCSCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCSCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.5 %

Procedure:
A solution of tetradecylsulfanyl-acetic acid (1.50 g, 520 mmol) in dry THF (10 ml) was added drop wise to a suspension of LiAlH4 (0.40 g, 10.4 mmol) in dry THF (30 ml) at 0° C. The mixture was stirred at 0° C. for one hour and then at ambient temperature for 18 hours. Saturated NH4Cl (40 ml) was added, and the resulting mixture was filtered through a short pad of celite. The phases were separated and the aqueous layer was extracted with diethyl ether (50 ml). The combined organic phases was washed with brine (50 ml), dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography on silica gel (heptane:EtOAc 4:1) afforded 0.76 g (54%) of the title compound as a colourless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][C:11]1[O:12][C:13]2[C:14](=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.CI.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:23][O:20][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]#[C:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[O:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2oc(CCC#Cc3ccccn3)nc12
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc2oc(CCC#Cc3ccccn3)nc12
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A mixture of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol (20 mg, 76 μmol, Example 70), methyl iodide (57 μL, 114 μmol) and K2CO3 (18 mg, 130 μmol) in DMF (2 mL) was stirred under reflux for 3 h. The reaction mixture was then allowed to cool to room temperature and was dissolved in DCM. The organic phase was washed with water, HCl 1N; saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 10 mg (36 μmol, 47%) of 4-methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[NH:9][CH2:10][CH2:11][N:12]2[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:6].N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:5](=[O:6])[C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[CH:3]=2)[N:12]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10]1)=[O:39]
Reactant: O=C(Br)CBr
Reactant: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1cccc(Cl)c1)c1cccc2c1N(C(=O)CBr)CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of benzyl 5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1D (50 g, 123 mmol) in DCM (500 mL) at 0° C. was added pyridine (14.91 ml, 184 mmol). Bromoacetyl bromide (26.7 ml, 307 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with H2O, saturated NaHCO3, and brine, dried over Na2SO4, filtered, concentrated to afford benzyl 4-(2-bromoacetyl)-5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1E (55 g, 104 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.0 (1H, bs), 7.85 (1H, s), 7.75 (1H, m), 7.6 (2H, m) 7.4 (7H, m), 7.10 (1H, m), 5.3 (2H, s), 4.15 (2H, m), 4.0 (2H, m), 3.8 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.ClC1C=CC([N+]([O-])=O)=CC=1O>>[N:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:3][CH:4]=2)[N:12]=[N:11][CH:10]=1
Reactant: Brc1ccc(-n2ncnn2)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: O=C(O)c1ccc(-c2ccc(-n3ncnn3)cc2)cc1

Procedure:
The title compound was prepared from 2-(4-bromophenyl)tetrazole (D72, 0.2 g) and 4-boronobenzoic acid (0.15 g) as described in Description 15 (0.17 g, 72%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.F[C:23]1[C:28]([F:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:29][C:28]1[C:23]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[N:17]=[CH:18][CH:19]=[N:20]2)=[N:24][CH:25]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:27]=1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 65 mg, 0.36 mmol) and DIPEA (42 mg, 0.33 mmol) in dry DMSO (1.1 ml) was subjected to microwave irradiation at 140° C. for 1 hour. The reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]2[NH:19][CH:18]=[N:17][C:16]=2[CH3:20])[N:5]=1)C>Cl>[CH3:20][C:16]1[N:17]=[CH:18][NH:19][C:15]=1[CH2:14][S:13][CH2:12][CH2:11][NH:10][C:6]1[NH:5][C:4](=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: CCOc1cccc(NCCSCc2[nH]cnc2C)n1
Agent: Cl
Product: Cc1nc[nH]c1CSCCNc1cccc(=O)[nH]1
Reaction time: 8 h

Procedure:
A solution of this ethoxypyridine (3.4 g. of base) in 5 N hydrochloric acid (100 ml) was heated under reflux for 21/2 hours. The reaction mixture was evaporated to dryness, the residue dissolved in a minimum amount of water, the solution basified with aqueous potassium carbonate, washed once with chloroform, and allowed to stand at 0° overnight. Crystals of 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-6-one were collected and recrystallised from water to give the pure product, m.p. 85°.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:31]=[CH:30][C:12]2[C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)=[N:14][S:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:31]=[CH:30][C:12]2[C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:22]3[CH:27]=[CH:26][C:25]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:24][CH:23]=3)=[O:29])=[N:14][S:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)NCCCNc3nsc4cc(S(=O)(=O)NC(C)(C)C)ccc34)cc2)cc1
Yield: 34.2 %

Procedure:
A mixture of N-(3-(6-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)4-iodobenzamide (50 mg, 0.09 mmol), 4-methoxyphenylboronic acid (14 mg, 0.09 mmol), tetrabutylammonium bromide (29 mg, 0.09 mmol), sodium carbonate (29 mg, 0.27 mmol) and palladium (II) acetate (1 mg) in water (3 mL) was microwaved at 160° C. for 5 min. The reaction was diluted with methylene chloride and the mixture was washed successively with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 98:2 methylene chloride:methanol yielded N-(3-(6-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4′-methoxybiphenyl-4-carboxamide (17 mg), as a white solid. 1H NMR (300 MHz, DMSO-d6): 8.70 (s, 1H), 8.52 (t, 1H), 8.10 (d, 1H), 7.86 (d, 2H), 7.81 (t, 1H), 7.68 (t, 3H), 7.52-7.60 (m, 2H), 6.97-7.08 (m, 2H), 3.80 (s, 3H), 3.49-3.57 (m, 4H), 1.95 (t, 2H), 1.12 ppm (s, 9H). MW=553 confirmed by LC-MS, tr=4.30 min (Method B) MH+=554.
Reaction SMILES: C(O[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:27][CH2:28][CH2:29][NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(C)(C)C.[ClH:38]>O1CCOCC1.C(OCC)C>[ClH:38].[ClH:38].[ClH:38].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:27][CH2:28][CH2:29][NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide (Method 20, 64 mg, 0.120 mmol) was suspended in 1,4 dioxane (1.5 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (1 ml) added. The reaction mixture was stirred at ambient temperature for 64 hours. The reaction mixture was diluted with diethyl ether, and the resultant precipitate was collected by filtration, washed with diethyl ether and air dried, to yield the title compound (as its hydrochloride salt) as an off white solid (62 mg, 95%); Mass Spectrum: M+H+ 433.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:3]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:15][CH:9]([CH3:10])[C:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: CCC(=O)c1cc(C)ccn1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(C(=O)C(C)Cl)c1

Procedure:
To a stirred solution of 1-(4-methylpyridin-2-yl)propan-1-one (0.9 g) in chloroform (5 ml) was added a solution of sulfuryl chloride (0.533 ml) in chloroform (5 ml) dropwise. The resultant mixture was refluxed for 2 hours and evaporated under reduced pressure. The pH was adjusted to 8.5 with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:dichloromethane=1:1) to give 2-chloro-1-(4-methylpyridin-2-yl)propan-1-one (0.71 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:16].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(C(=O)CCCC(C)C)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(O)CCCC(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
1-(4-Bromo-3-methyl-phenyl)-5-methyl-hexan-1-one (3.5 g, 12.4 mmol) was dissolved in ethanol and cooled to 0° C. while stirring under nitrogen. To the flask was added sodium borohydride (469 mg, 12.4 mmol), and the reaction was kept at 0° C. for 1 h., then slowly warmed to room temperature. The reaction was monitored by HPLC. Upon complete consumption of starting material, the reaction is carefully quenched with water, the ethanol removed by rotary evaporator, and extracted with diethyl ether, washed, dried, and concentrated. The title compound (3.33 g, 11.72 mmol), is used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:33])[C:19]([C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:39].C(O)C>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:33])[C:19]([C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:39]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1

Procedure:
0.385 g of the acid of Example 32 was added to 1 ml of a molar solution of sodium acetate in methanol to obtain a lipid solution to which 5 ml of ethanol were slowly added. The mixture was vacuum filtered and the recovered product was rinsed with ethanol and then ether to obtain 0.215 g of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (11.6 g), tosyl chloride (11.44 g), and pyridine (60 mL) was stirred at room temperature for over-night. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 1 M hydrochloric acid solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (16.94 g, 85%) as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1>C(Cl)Cl.C(OC=C)(=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1
Reactant: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Solvent: C=COC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1
Reaction time: 28 h

Procedure:
490 g of the crude, racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate (see Example 1) were dissolved in 3.1 l of methylene chloride and 850 ml of vinyl acetate, admixed with 18 g of Novozym 435 and stirred at 21–24° C. After 28 h, a further 2 g of Novozym 435 were added. After a total of 44 h, the reaction was ended by filtering off the enzyme and the filtrate was concentrated by evaporation under reduced pressure to obtain 540 g. Chromatography of the residue on approx. 6 kg of silica gel (1:1 ethyl acetate/n-heptane) gave 184 g of methyl (1R,3S)-2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate; >98% ee (HPLC on Chiralpak AD-H 250×4.6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0.5+0.1% TFA); 1H NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H) and 239 g of the (1S,3R)-acetate (93% ee, HPLC on Chiralcel OD/20 250×4.6, 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH2:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[CH2:11]>C1C=CC=CC=1>[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([N:26]=[CH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[CH2:11]
Reactant: Cc1cccc(C=O)n1
Reactant: C=Cc1ccc([C@@H](N)Cc2ccccc2)cc1
Solvent: c1ccccc1
Product: C=Cc1ccc([C@H](Cc2ccccc2)N=Cc2cccc(C)n2)cc1

Procedure:
A solution of 0.54 g (4.5 mmol) of 6-methyl-pyridine-2-carbaldehyde, 1.0 g (4.5 mmol) of (S)-1-(4-vinylphenyl)-2-phenyl-ethylamine and 10 ml of benzene is evaporated down at room temperature and under about 3 kPa. A further 10 ml of benzene are added in order to distill off residual water of reaction together with benzene under about 3 kPa. The process is repeated twice more.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([CH:13]2[CH2:30][CH2:29][C:16]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][N:10]=[CH:9]1>>[N:8]1([CH:13]2[CH2:30][CH2:29][C:16]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(n3ccnc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cn(C2CCC3(CCNCC3)CC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2 ml) was added to a solution of tert-butyl 9-(1H-imidazol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.10 g, 3.45 mmol, 1.0 eq.) in MC (10 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped twice with MC to get the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[C:12](OC)([CH3:14])[CH3:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:13][C:12]1([CH3:14])[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: CC(CO)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(C)(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a mixture of 3-hydroxy-2-hydroxymethyl-2-methylpropionic acid (6.71 g, 50 mmol), dimethoxypropane (7.99 mL, 65 mmol) and acetone (50 mL), p-toluenesulfonic acid hydrate (0.048 g, 0.25 mmol) was added and the resulting mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, sodium bicarbonate (0.1 g) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 5 minutes and concentrated in vacuo. To the resulting residue was added water and the resulting mixture was extracted with ethyl ether. The extract was dried over anhydrous sodium sulphate and concentrated in vacuo to give 2,2,5-trimethyl-1,3-dioxane5-carboxylic acid (7.87 g, yield: 90%) as colorless oil.