Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:30])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:30])=[CH:39][CH:40]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc21
Yield: 62.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.05 g (0.17 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75), to give 0.051 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-147).
Reaction SMILES: [Na].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>>[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Reactant: COCCO
Agent: O=C(O)C(=O)O
Agent: [Na]
Product: COCCOc1nsnc1C1=CCCN(C)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate (310 mg, 1 mmol). The mixture was stirred at 50° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The title compound was crystallized as the oxalate salt from acetone to yield 270 mg. (M.p. 152.1° C.; M+ : 253; Compound 15).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[S:21]([O:8][CH2:7][C:3]1([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1(CO)COC1
Solvent: O
Solvent: c1ccncc1
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 0 °C

Procedure:
3-ethyl-3-hydroxymethyloxetane (trade name of product, OXT-101®, manufactured by To a Gosei Co.; 116 g) was added to pyridine (500 mL) and cooled to 0° C. while stirring. p-Toluene sulfonyl chloride (190 g) was added divisionally for several times. After stirring for 5 hours while keeping at 0° C., the reaction mixture was poured to iced water (1 L). It was extracted with diethyl ether (500 mL), the pH was rendered acidic with 3% hydrochloric acid, and extracts were washed with water. Then, the extracts were washed with a saturated solution of sodium carbonate and water successively and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3-[(tosyloxy) methyl]3-ethyloxetane (243 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10](=O)[CH3:11].OS(O)(=O)=O.[N:18]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([Cl:8])[CH:6]=1)[NH:1][N:18]=[C:10]2[CH3:11]
Reactant: CC(=O)c1cc(Br)cc(Cl)c1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1n[nH]c2c(Cl)cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a 0° C. solution of 1-(2-amino-5-bromo-3-chlorophenyl)ethanone (206 mg, 0.83 mmol) in 50% aqueous solution of concentrated H2SO4 was slowly added NaNO2 (73 mg, 1.0 mmol). The cooling bath was removed following the addition of NaNO2, stirred at room temperature for 1 hour and then recooled to 0° C. before addition of SnCl2.2H2O (573 mg, 2.49 mmol). The mixture was stirred at 0° C. for 1 hour before dilution with water. The solids were collected by vacuum filtration to afford 5-bromo-7-chloro-3-methyl-1H-indazole (130 mg, 64%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21](=[O:30])/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1COCC1>[OH:30][CH:21]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CCCCCC/C=C\C=O
Reactant: C#C[Si](C)(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC/C=C\CC(O)C#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Trimethylsilylacetylene (6.9 g, 48.6 mmole) is dissolved in 125 ml dry THF in a flamed dried 500 ml 3-neck round bottom flask under nitrogen at -78° C. The solution is treated with n-butyllithium (29.9 ml, 46.3 mmole) slowly dropwise over 10 minutes and stirred 30 minutes at -78° C. The reaction mixture is subsequently treated slowly dropwise with boron trifluoride etherate (6.0 ml, 48.8 mmole) and the resultant mixture is stirred 20 minutes at -78° C. 3-Z-Nonenal (6.2 g, 44 mmole), in 3×12 ml dry THF, is added rapidly dropwise to the reaction mixture at -78° C. The reaction is warmed to 0° C. and stirred an additional 20 minutes. The mixture is quenched with 100 ml saturated sodium chloride, the layers separated, and the aqueous phase extracted with 3×60 ml diethyl ether. The organics are combined, dried over magnesium sulfate, and concentrated in vacuo to a dark yellow oil (10.5 g). The crude oil is chromatographed over 200 g silica gel (230-400 mesh), eluting with 6% ethyl acetate/hexane and collecting 60 ml fractions. Fractions 8-16 are combined and concentrated to afford 6.3 g of the title compound as a pale yellow oil. Following the above procedure gives the title compound having the physical characteristic described below:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]([CH2:19][CH3:20])[S:17][C:16](=[O:21])[NH:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])F.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29]O[CH2:27][CH2:26]1>>[N:25]1([CH2:30][CH2:29][N:15]2[N:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]([CH2:19][CH3:20])[S:17][C:16]2=[O:21])[CH2:26][CH2:27][CH2:23][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: CCC1SC(=O)NN=C1c1ccc(OC(F)F)c(OC)c1
Product: CCC1SC(=O)N(CCN2CCCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
of 5-(3-methoxy-4-difluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-2-morpholinoethane:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](C2C=CC=CC=2)(O)[C:7]([OH:9])=[O:8])=[CH:2]1.CC(=O)OCC.[BrH:23]>C(O)(=O)C>[Br:23][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccsc1
Reactant: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)C(Br)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (thiophen-3-yl)mandelic acid (8.60 g, 54.4 mmol) was dissolved in 100 ml of 30% HBr in acetic acid. The solution was stirred for 18 hours at RT. The clear black solution was poured onto 2.5 L of ice water and immediately extracted with Et2O (4×400 ml). The ether was dried over Na2SO4 and treated with decolorizing carbon. The Et2O was evaporated and the residue was azeotroped with toluene to remove residual acetic acid. The crude solid product was recrystalized from hexanes to yield 9.07 g. (75.%). EA, MS(FD).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]3[CH:31]=[N:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A solution of Example A1 (0.525 g, 2.086 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.551 g, 2.504 mmol) in dioxane (16 mL) was sparged with Ar, treated with a solution of K2CO3 (0.577 g, 4.17 mmol) in water (4 mL) and heated at 90° C. for 1 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with 60% EtOAc/Hex, sonicated and the resulting solid collected via filtration to afford 4-((6-nitropyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-amine (580 mg, 90%) as a dark orange solid. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J=2.5 Hz, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.40 (dd, J=8.9, 0.5 Hz, 1H), 8.06 (dd, J=8.7, 2.5 Hz, 1H), 7.96 (dd, J=8.9, 2.8 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.02 (dd, J=5.6, 2.3 Hz, 1H), 6.48 (dd, J=8.7, 0.7 Hz, 1H), 6.32 (s, 2H); MS (ESI) m/z: 310.1 (M+H+).
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Si]([N:21]=[N+:22]=[N-:23])(C)C>C1(C)C=CC=CC=1>[N:21]([C:11]1([CH3:10])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:22]=[N-:23]
Reactant: CC1(O)CCCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(N=[N+]=[N-])CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
BF3.Et2O (934 mg, 6.23 mmol) was added drop-wise at 20° C. to a stirred solution of 1-methylcyclopentanol (520 mg, 5.19 mmol) and trimethylsilyl azide (716 mg, 6.23 mmol) in 6 mL of toluene. Then the solution was stirred at room temperature for 16 hours. The organic phase was washed with a 10% solution of NaHCO3 (10 mL), water (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was evaporated at 35° C. under reduced pressure to give 1-azido-1-methylcyclopentane (720 mg) as a crude product. It was used directly in the next step without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1)(=O)=O.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])[N:8]=1
Reactant: O=S(=O)(Oc1cccc(Cl)n1)C(F)(F)F
Reactant: C[Sn](C)(C)Cl
Product: C[Sn](C)(C)c1cccc(Cl)n1

Procedure:
6-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used in Procedure I with trimethyltin chloride to yield 2-chloro-6-(trimethylstannyl)pyridine. The crude material (˜4 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2 mmol). Purified by silica gel chromatography (545% ethyl acetate/hexane) to yield N-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.45 (25% ethyl acetate/hexanes); MS (Q1) 426 (M)+.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](Cl)=[O:17])[CH3:11].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](=[O:17])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1)[CH3:11]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: C[Si](C)(C)c1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-trimethylsilanyl-thiazole (2.6 g, 16.53 mmol) in DCM (30 mL) is added a solution of 3-chlorocarbonyl-propionic acid ethyl ester (5.4 g, 32.81 mmol) in DCM (10 mL). The mixture is stirred overnight at room temperature. To the mixture is added 5% NaHCO3 (30 mL) and mixture is stirred at room temperature for 20 minutes. The organic layer is separated and the aqueous lay is extracted with DCM (2×50 mL). The combined organic layers are dried and the solvent removed. The residue is separated by column (methylene chloride) to give 4-oxo-4-thiazol-2-yl-butyric acid ethyl ester.
Reaction SMILES: [CH:1]([O:14][C:15]([C@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH:36]=1)\[C:29](O)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>>[CH:1]([O:14][C:15]([C@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[S:35][CH:36]=1)\[C:29]([NH:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: O=C(O)/C(=N\O[C@@H](C(=O)OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(O)c(O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 100.7 %

Procedure:
By using 4.57 g (6 mmol) of (Z)-2-[[(R)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid, 2.03 g (5 mmol) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate, 1.39 ml (10 mmol) and 0.84 ml (6 mmol) of triethylamine and 0.75 ml (8 mmol) of phosphorus oxychloride, the treatment was conducted in the same manner as in Example 1 (A) to obtain 5.60 g (yield: 56%) of p-methoxybenzyl 7-[(Z)-2-[[(R)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate as a foam-like solid.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(Br)cc1Cl
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1Cl
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
To tetrahydrofuran (20 mL) at −100° C. was added tert-butyllithium (1.7M in pentane, 4.30 mL, 7.31 mmol) dropwise over 5 min. 4-Bromo-2-chloro-1-methoxybenzene (0.81 g, 3.66 mmol) dissolved in tetrahydrofuran (5 mL) was added over 10 min. The mixture was stirred for 5 min then was (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.241 g, 3.05 mmol) in tetrahydrofuran (10 mL) added over 10 min. The reaction mixture was held at −100° C. for 20 min and then slowly allowed to reach r.t. over night. Hydrogen chloride-methanol solution (14.63 mL, 18.29 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to give the title compound (570 mg, 42%). MS (ES+) m/z 445, 447 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:19]=[N:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][O:9][N:8]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>>[CH:25]1([CH2:24][NH:23][C:20]([C:17]2[N:18]=[N:19][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nn1
Product: O=C(NCC1CC1)c1ccc(OCc2conc2-c2ccccn2)nn1
Yield: 61 %

Procedure:
As described for example 123 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (70 mg, 0.24 mmol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (50 mg, 61%) which was obtained as an off white solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.[CH:19](O)(C)C>[Pd]>[CH3:3][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: CC(C)O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: Cc1c(C(=O)OC(C)C)[nH]c2ccccc12
Yield: 25 %

Procedure:
Sodium borohydride (0.23 g) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (0.2 g) and 10% palladium on carbon (0.11 g) in isopropanol (45 ml). The solution was heated at reflux for 4 hours, cooled and filtered through Celite. The solution was partitioned between ethyl acetate and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give the desired end product as a white solid (0.05 g, 25%); NMR δ (CD3SOCD3) 1.3 (d, 6H), 2.5 (s, 3H), 5.2 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.6 (d, 1H), 11.3 (bs, 1H).
Reaction SMILES: [CH2:1]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[C:11]([NH2:16])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH2:1]([O:7][C:8](=[O:17])[C:9]1[CH:10]=[C:11]([NH:16][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[CH:12]=[C:13]([NH:15][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCOC(=O)c1cc(N)cc(N)c1
Product: CCCCCCOC(=O)c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 82 %

Procedure:
Using n-hexyl-3,5-diaminobenzoate (24.0 g, 101.7 mmol) and 4-nitrobenzoyl chloride (39.7 g, 214.4 mmol), n-hexyl[3,5-bis(4-nitrobenzoylamino)]benzoate was obtained (44.5 g, yield: 82%) in the same manner as in Example 1.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:8]([O:10]C)=O)[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[NH2:22][C@H:23]([C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH3:24]>>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:8]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH3:24])=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[OH:6]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
0.2 ml of aqueous solution containing 2 mM Z-Glu-OMe, 50 mMH-Ala-Ala-OH, 25 mMNaOH and 5 mg/ml endoproteinase Glu-C are deep-frozen. Subsequently the reaction mixture is kept at -25° C. until the Z-Glu-OMe is consumed. Following thawing, the yield is determined analytically by RP-HPLC and amounts to 76% of theory.
Reaction SMILES: [C:1]([N:4]1[C:22](=[O:23])[NH:21][C:20](=[O:24])[C@@:5]21[O:9][C@@H:8]([CH2:10]I)[C@H:7]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]2[O:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2].[C:25]([O-:28])(=[S:27])[CH3:26].C[N+](C)(C)C>COCCOC.ClCCl>[C:1]([N:4]1[C:22](=[O:23])[NH:21][C:20](=[O:24])[C@@:5]21[O:9][C@@H:8]([CH2:10][S:27][C:25](=[O:28])[CH3:26])[C@H:7]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]2[O:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(=O)O[C@H]1[C@H](CI)O[C@]2(C(=O)NC(=O)N2C(C)=O)[C@@H]1OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)O[C@H]1[C@H](CSC(C)=O)O[C@]2(C(=O)NC(=O)N2C(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Yield: 94.4 %

Procedure:
To a solution of (2R, 3R, 4R, 5S)-6-acetyl-2-iodomethyl-3, 4-diacetoxy-1-oxa-6,8-diazaspiro (4,4) nonane-7, 9-dione (598 mg, 1.32 mm) in anhydrous DME (10 ml) is added, under N2, tetramethylammonium thioacetate (353 mg, 2.37 mm) in one portion. The resulting mixture is heated at 45° C. for 4 hours, then diluted with dichloromethane and washed with brine, dried, and evaporated for dryness. The crude product is purified by thin-layer chromatography to give (2R, 3R, 4R, 5S)-6-acetyl-2-acetylthiomethyl-3, 4-diacetoxy-1-oxa-6, 8-diazaspiro (4,4) nonane-7, 9-dione (500 mg) as a hygroscopic foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[I-].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Clc1nc2ccccc2s1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(COc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (300 mg, 1.39 mmol) was dissolved in N,N-dimethylformamide (5 mL). While this solution was chilled in an ice bath, 60% sodium hydride in oil (83.6 mg, 2.09 mmol) was added. The reaction mixture was stirred for 10 min while ice-chilled and for another 10 min at room temperature. 2-chlorobenzothiazole (0.344 mL, 2.78 mmol) and sodium iodide (208 mg, 1.39 mmol) were then added and the mixture was stirred at room temperature for 5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine. The washed product was then dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 460 mg (95%) of the desired compound as a colorless powder.