Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>C(O)C.[Pd]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCOc1ccc(N)cc1
Yield: 89.9 %

Procedure:
A solution of 42.5g (0.2 mole) of N, N-dimethyl-2-(4-nitrophenoxy)ethanamine in 200 ml of ethanol is divided and reduced in a Parr apparatus using 2g of 5% palladium/charcoal in 50 ml of ethanol for each of the two reactions. The combined mixtures are filtered, the solvent is evaporated and the residue is distilled to give 32.4g (90%) of oil, boiling point 145°-148° C/0.7 mm of Hg. This material solidifies into needles, melting point 48°-50° C.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6](=[O:20])[C@:7]([NH:18][NH2:19])([CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)(O)=O.Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:40]=CC=1)[C:26]([O:28]CC1C=CC(OC)=CC=1OC)=[O:27]>>[OH:16][C:11]1[CH:10]=[C:9]([CH2:8][C@@:7]([NH:18][NH2:19])([CH3:17])[C:6]([O:5][CH2:4][C:1]2[CH:40]=[C:25]([CH:24]=[CH:23][CH:22]=2)[C:26]([OH:28])=[O:27])=[O:20])[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCC(=O)O
Reactant: COc1ccc(COC(=O)c2cccc(CCl)c2)c(OC)c1
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCc1cccc(C(=O)O)c1
Yield: 26 %

Procedure:
Following the procedure described for preparation of compound 229, and substituting tert-butyl bromomethyl acetate with 2,4-dimethoxybenzyl m-chloromethyl-benzoate, provided the title compound (26% over 2 steps) as a white solid. 1H NMR (400 MHz, CD3OD): δ1.42 (3H, s), 2.79 (1H, d), 2.90 (1H, d), 5.2 (2H, m), 6.35 (1H, dd), 6.56 (1H, d); 6.60 (1H, d), 7.45 (2H, m), 7.97 (2H, m). MS (ESI) m/z 361.15 (M+H+) and 359.17 (M−H−).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:25][O:26][C:27]([C:29]1([CH2:35][NH2:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>CO>[CH3:25][O:26][C:27]([C:29]1([CH2:35][NH:36][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: COC(=O)C1(CN)CCOCC1
Solvent: CO
Product: COC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCOCC1

Procedure:
After a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (151 mg), 4-aminomethyl-tetrahydro-pyran-4-carboxylic acid methyl ester (205 mg; commercially available) in MeOH (2 mL) was microwaved at 150° C. for 500 min; cooled, concentrated, the residue was partitioned between EtOAc and diluted HCl solution, EtOAc phase was washed with water and diluted NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated and column purified to give product (154 mg). LC MS ESI+: 462 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 60.9 %

Procedure:
A mixture of 2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.06 ml), water (0.06 ml) and ethanol (30 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 5-guanidinoimino-2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 83) (0.25 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH:24]=[CH2:25])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH:24]=[CH2:25])=[CH:26][CH:27]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C=C)cc2)c1
Product: C=CCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C=C)cc2)c1

Procedure:
The product from Example 87A and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 529 (M+H)+.
Reaction SMILES: N.[Li].[CH2:3]1[CH2:16][O:15][C:10]23[O:11][CH2:12][CH2:13][O:14][C:5]2([C@:6]2([CH2:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[C:26]4[C@@H:17]([CH2:18][CH:19]=[C:20]5[C@@H:25]4[CH2:24][CH2:23][CH2:22][CH2:21]5)[C@@H:8]2[CH2:9]3)[CH3:7])[O:4]1.O>O1CCCC1>[CH2:13]1[CH2:12][O:11][C:10]23[O:15][CH2:16][CH2:3][O:4][C:5]2([C@:6]2([CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[C@H:26]4[C@@H:17]([CH2:18][CH:19]=[C:20]5[C@@H:25]4[CH2:24][CH2:23][CH2:22][CH2:21]5)[C@@H:8]2[CH2:9]3)[CH3:7])[O:14]1
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Reaction time: 0.33 h

Procedure:
800 ml of ammonia are condensed at -70° C. and 1.39 g of lithium are added. After the characteristic blue colouring appears, 18.6 g (40 mmol) of 3,3;17,17-bis-(ethylenedioxy)-11-(4-methoxyphenyl)-5,9(11)-oestradiene dissolved in 400 ml of tetrahydrofuran are added dropwise. After stirring the mixture for 20 minutes, the excess lithium is decomposed by the addition of water, and the ammonia is evaporated off. The reaction mixture is poured onto saturated ammonium chloride solution and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. After chromatography of the crude product on silica gel with a mixture of ethyl acetate/hexane, 15.2 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-oestrene and 1.4 g of 17,17-bis-(ethylenedioxy)-11-(4-hydroxyphenyl)-5, 9(11)-oestradiene, m.p. 168°-170° C. (ethyl acetate), [α]D20 =-11° (CHCl3 ; c=0.505), are isolated in the form of white foams.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5](Cl)=[CH:4][CH:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1>CN1C(=O)CCC1.C(N(C(C)C)CC)(C)C>[C:13]([CH:12]1[CH2:11][CH2:10][N:9]([C:5]2[N:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cc1ccc(Cl)nn1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2ccc(C)nn2)CC1
Yield: 44 %

Procedure:
55 mmoles of 6-methyl-3-chloropyridazine was added to 75 mmoles of ethyl isonipecotate in 5 mL NMP and 20 mL diisopropylethylamine (DIPEA) and refluxed for 6 hours. The product was isolated as described in Example 1a above to give a 44% yield of 3-(4-carboethoxy-1-piperidinyl)-6-methylpyridazine. Reduction of 18.8 mmol of this compound using 56.6 mmol DIBAL in 100 mL THF with a Rochelle's salt quench gave 3-(4-hydroxymethyl-1-piperidinyl)-6-methylpyridazine (Formula IV: R1 =CH3 ; Y=CH2) which was used unpurified in the final step. Reaction of 5 mmol of the product described in Example 1b with 4.5 mmol of the 3-(4-hydroxymethyl-1-piperidinyl)-6-methyl pyridazine according to the procedure of Example 1c afforded after recrystallization from ethyl acetate at -70° C. the compound of formula I (R1 =R4 =CH3, Y=CH 2, R2 =R3 =hydrogen) in 12% yield, m.p. 180°-185° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]([O:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[C:17]([O:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-(1-Methylpiperazin-4-yl)benzoic acid (250 mg, 1.13 mmol) and 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 331 mg, 1.59 mmol) were dissolved in DMF (3 ml). 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18, 313 mg, 1.13 mmol) was added and the resulting solution was stirred for 20 hours at ambient temperature. The solution was poured into water and extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (eluting with 99:1→9:1 dichloromethane:methanol) to afford the title compound as a colourless gum which crystallised on trituration (240 mg, 52%); Mass Spectrum: M+H+ 411.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[OH:10])#[N:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH2:11][CH:13]1[O:15][CH2:14]1)#[N:2]
Reactant: ClCC1CO1
Reactant: N#Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(Cl)cc1OCC1CO1
Yield: 75.7 %

Procedure:
2-Cyano-5-chlorophenol (3.0 g), epichlorohydrin (6.0 g) and anhydrous potassium carbonate (4.2 g) were heated with stirring in ethanol for 2 hours. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3.1 g of 1-(2-cyano-5-chlorophenoxy)-2,3-epoxypropane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Yield: 51.4 %

Procedure:
To a 100 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (2.02 g, 7.5 mmol) followed by a addition of anhydrous THF (60 mL) under an atmosphere of nitrogen. Benzhydrazide (1.02 g, 7.5 mmol) was subsequently added and the mixture was cooled to −15° C. To this mixture was added HOBt (1.02 g, 7.5 mmol) followed by addition of EDC (2.88 g, 15.0 mmol) and lastly, TEA (3.2 mL, 23 mmol) was slowly added. The temperature of this reaction was maintained between −25° C. and −15° C. for a period of 1 h then allowed to warm to room temperature overnight. The solids were filtered off and washed with additional THF (20 mL) and EtOAc (20 mL). The mother liquor was then diluted with EtOAc (200 mL) and washed with 5% citric acid/water (2×50 mL), saturated sodium bicarbonate (1×25 mL), and brine (1×50 mL) then dried over sodium sulfate. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a white solid. This was purified via silica gel chromatography eluted with 85% EtOAc/hexane to provide title compound as a white solid (1.49 g, 51%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.64 (br s, 2H), 7.94 (m, 2H), 7.60 (m, 1H), 7.51 (m, 3H), 6.73 (d, J=8.7 Hz, 1H), 5.59 (d, J=7.2 Hz, 1H), 4.71 (br s, 1H), 4.24 (m, 1H), 4.12 (dd, J=5.1, 7.3 Hz, 1H), 2.35 (s, 3H), 1.39 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2cccnc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccnc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-16; 0.92 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.01 mmol), potassium carbonate (3.67 mmol) in DMF (5 mL). The product was triturated from Et2O, mp 122-125° C. MS (APCI): 470 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:32][CH:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1>C(O)C>[C:40]([O:39][C:37]([N:35]1[CH2:36][CH:33]([NH:32][C:20]([C:17]2[N:16]=[C:15]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11][C:12]([OH:14])=[O:13])[O:19][N:18]=2)=[O:22])[CH2:34]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 80 °C

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (480 mg, 1.42 mmol) and triethylamine (1 ml, 7.18 mmol) in ethanol (8 ml) was treated with tert-butyl 3-amino-1-azetidinecarboxylate (Preparation 78) (300 mg, 1.74 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 18 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (90:10) to afford the title compound contaminated with starting amine. The solid was dissolved in ethyl acetate and washed with hydrochloric acid (0.5M) (2×), water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a sticky foam.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])C)(C)(C)C>ClCCl>[CH3:13][NH:14][C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
At 0° C., trifluoroacetic acid (5 ml) was added to a solution of N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamic acid tert-butylester (913 mg, 2.67 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 15 min at 0° C. The solvent was removed in vacuo without warming. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (20 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 658 mg of N-((2R)-2-methylamino-3-phenylpropyl)methansulfonamide.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]([CH2:19][C:20]([OH:22])=[O:21])[CH2:3]1.[Li+].[OH-].[CH3:25][CH2:26]OC(C)=O>O1CCOCC1.CO>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]([CH2:19][C:20]([O:22][CH2:25][CH3:26])=[O:21])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)O)cc1
Reactant: CCOC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)CC1CC(=O)NCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A solution of the product of step A (1.34 g, 5.44 mmol) was stirred in THF (30 ml) at 0*C. Bu3SnOTf (90%, 2.73 g, 5.60 mmol) in THF 8.0 ml was added dropwise over 6 min, and the mixture was heated to reflux for 22 h. The reaction was cooled to 0° C., and triethylamine (1.52 ml, 10.9 mmol) and dimethylaminopyridine (0.135 g, 1.11 mmol) were added followed by p-toluenesulfonyl chloride (2.09 g, 11.0 mmol) in THF 4.0 ml. The reaction was allowed to r.t. and after 4 h concentrated under reduced pressure. AcOEt (100 ml) was added to the residue and washed with 0.1 N HCl aq. (100 ml×2), sat'd NaHCO3 aq. (100 ml×2) and sat'd NaCl aq. (100 ml×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (AcOEt→AcOEt/-MeOH=80/1) to yield the title compound. MS:355.2 C. 2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (3) To a solution of the product of step B (0.416 g, 1.17 mmol) in 1,4-dioxane (24 ml) and MeOH (24 ml), 0.13 N LiOH (28 ml, 3.6 mmol) was added, and the mixture was heated to reflux for overnight. The reaction was cooled to r.t. and AcOEt (400 ml) was added and washed with sat'd NaCl (400 ml×5), dried over Na2SO4 and concentrated under reduced pressure to yield the title compound. MS: 327.1 D. (R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide. To a mixture of 2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (0.115 g, 0.352 mmol), (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (0.0945 g, 0.387 mmol) and HOBt (<5% H2O, ˜0.398 mmol) in DMF (3.0 ml) was added EDCI*HCl (0.0805 g, 0.420 mmol), and stirred overnight under N2. AcOEt (60 ml) was added and washed with sat'd NaHCO3 aq. (60 ml×3) and sat'd NaCl aq. (60 ml×3), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (CH2Cl2/MeOH with 2N NH3=10/1) to yield the title compound. MS: 553.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:5]1.[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[O:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28]([NH:1][CH2:2][CH2:3][CH:4]2[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:5]2)=[O:29])[O:24]1
Reactant: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-aminoethyl)morpholine-4-carboxylate (Example 11, step 2) (178 mg, 0.534 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (68.9 mg, 0.534 mmol), T3P® (50% in DMF) (510 mg, 0.801 mmol), Huenig's base (466 μl, 2.67 mmol) in DMF (1781 μl) was stirred at room temperature. Another 1 equivalent of 2-oxo-2,3-dihydrooxazole-5-carboxylic acid was added and the reaction mixture was left stirring at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The organic portion was dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dried loaded using silica onto an ISCO 4 g column eluting with 0-100% EtOAc (1% acetic acid) in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13][OH:14])=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[N:9]([CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(CCO)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCO)CC1
Yield: 70.1 %

Procedure:
28 g of 7-chloro-6-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 40 g of 1-methyl piperazine and 200 cm3 of pyridine were heated for 18 hours under reflux. The solvent was removed by distillation under reduced pressure. The residue was taken up in 100 cm3 of water, the mixture was agitated and adjusted to pH 6.8 by the addition of acetic acid. The solid was filtered off, washed with water and recrystallised from DMF. 24 g of 6-fluoro-1-(2-hydroxyethyl)-7-(4-methyl-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p. 270° C., were obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33].B(Br)(Br)Br>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: BrB(Br)Br
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 12.6 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 2, 112 mg of imine is reacted by reaction with 0.36 ml of BBr3 (1 M in dichloromethane), and 38 mg of the title compound is obtained.