Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9])[NH2:2].[CH:16](O)=O>>[CH3:9][C:8]1[C:3]2[N:4]([CH:16]=[N:2][N:1]=2)[N:5]=[C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:7]=1
Reactant: O=CO
Reactant: Cc1cc(N2CCOCC2)nnc1NN
Product: Cc1cc(N2CCOCC2)nn2cnnc12

Procedure:
20 Grams of 3-hydrazino-4-methyl-6morpholinopyridazine are dispersed in 200 milliliters of 99 percent aqueous formic acid. The mixture is heated at the boiling temperature under reflux and then concentrated until an oily residue remains in the reaction vessel. The residue is taken up in aqueous sodium carbonate solution, and the aqueous mixture is extracted with chloroform. The chloroform extract is dried with anhydrous sodium sulfate, then evaporated under reduced pressure to obtain the 8-methyl-6-morpholino-s-triazolo[4,3-b]pyridazine product as the free base. The product is recrystallized twice from isopropanol and found to melt at 177°-178° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15])([O-:7])=[O:6]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][S:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])(=[O:15])=[O:16]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 76 %

Procedure:
A solution of ethylene diamine (268 mL, 20 equiv) in DCM (400 mL) was added to an ice-cooled solution of o-nitrobenzene sulfonyl chloride (44.4 gm, 0.2 mole) in DCM (200 mL) over 1 hr. Concentration on the rotary evaporator left an oil which was partitioned between DCM and sat. aq. Na2CO3 solution. The aqueous phase was backextracted with DCM and the combined organic phases were dried (Na2SO4). Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0, 5, 10, 20, 30% MeOH) afforded the title compound as an oil (37.2 gm, 76%). 1H NMR (CDCl3+D2O) δ 2.82 (t, 2H, J=5.1 Hz), 3.10 (t, 2H, J=5.1 Hz), 7.73 (m, 2H), 7.83 (m, 1H), 8.11 (m, 1H); MS: 246 (M+H)+; HPLC Ret Time: 0.39 min (YMC Xterra 3.0×50 mm S7 C18 column, 3 min gradient, 4 mL/min).
Reaction SMILES: CO.[C:3]([O:11][CH2:12][C@@:13]1([C:32]#[CH:33])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@H:14]1OS(C)(=O)=O)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.CC(OC(C)=O)=O>C1COCC1.CO.CN(C1C=CN=CC=1)C>[C:3]([O:11][CH2:12][C@@:13]1([C:32]#[CH:33])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH:15]=[CH:14]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C#C[C@@]1(COC(=O)c2ccccc2)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: -70 °C
Yield: 127.9 %

Procedure:
A mixture of NaBH (628 mg, 16.6 mmol) and MeOH (50 ml) was cooled and stirred at −70° C. To this was added a mixture of 5 (3.39 g, 8.3 mmol) and CeCl3.7H2O (3.1 g, 8.3 mmol) in THF/MeOH=1/1 (50 ml) dropwise over 15 min. The resulting suspension was stirred for 1 h at the −70□. The reaction was quenched by adding AcOH (ca. 1 mL). The reaction mixture was evaporated. The residue was suspended in MeCN (15 ml). To this suspension were added DMAP (1.02 g, 8.3 mmol), i-Pr2NEt (1.45 mL, 8.3 mmol) and Ac2O (1.57 mL, 16.6 mmol). The mixture was stirred for 30 min at 0° under positive pressure of dry Ar, and partitioned between CH2Cl2 and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4), evaporated, and chromatographed on a silica gel column (hexane/EtOAc=4/1). This gave 6 (3.74 g, 100%) as an oil.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH:28]2[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:20][CH:19]=1>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: Nc1ccc(OS(=O)(=O)C2CC2)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: O=C1N(c2ccc(OS(=O)(=O)C3CC3)cc2)CCC12CCC(O)CC2

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with cyclopropanesulfonic acid 4-amino-phenyl ester as a mixture of cis and trans diastereomers. MS (m/e): 366.137 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:22]([N:10]([CH3:11])[CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: c1ccncc1
Product: CC(=O)N(C)C(Cc1ccccc1N)c1sccc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
A stirred, ice water chilled solution of 5.07 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 40 ml of pyridine was treated dropwise with 2.25 g of acetic anhydride. The solution was stirred with cooling for 15 minutes and then at room temperature for 3 hours. After standing overnight, the reaction mixture was decanted into water (200 ml), treated with dichloromethane (100 ml) and basified with 10% sodium hydroxide solution. The aqueous phase was extacted with dichloromethane (150 ml), and the combined organic phase was filtered and concentrated. The resulting solid was stirred with toluene and evaporated to dryness. Recrystallization from propionitrile (14 ml) afforded 3.0 g of N-acetyl-2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 176°-181.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: CCc1ccc(-c2cncc(C(=O)OC)c2)cc1

Procedure:
32 g (148 mmol) of methyl 5-bromonicotinate and 27 g (178 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to the General Method 1A. Yield: 24 g (64% of theory)
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:17][CH:18]([C:22]1[O:27][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[C:24]=2[N:23]=1)[CH:19]([CH3:21])[CH3:20].Cl>O1CCCC1>[Cl:17][CH:18]([CH:19]([CH3:21])[CH3:20])[C:22]([NH:23][C:24]1[C:32]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](=[O:28])[CH:10]([C:9]([NH:8][C:4]1[S:3][CH:7]=[CH:6][N:5]=1)=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:27]
Reactant: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CCOC(=O)CC(=O)Nc1nccs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Nc1nccs1)C(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)C(C)C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
Under an inert gas, 5.52 g of sodium hydride dispersed at 55% in oil and 173 ml of tetrahydrofuran were mixed together and then a solution of 26.22 g of ethyl 3-(2-thiazolylamino)-3-oxo-propanoate in 690 ml of tetrahydrofuran was added slowly at 20° C. After stirring for 10 minutes, a solution of 34.5 g of 2-(1-chloro-2-methylpropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared according to the process described in European Pat. No. 0040573] in 210 ml of tetrahydrofuran was added slowly at 20° C. After stirring at 20° C. for 35 minutes, the mixture was poured into 200 ml of 2N hydrochloric acid and was extracted with ether. The ethereal phase was washed with water, dried and the solvent was evaporated. The residue was triturated in ether and dried to obtain 42.35 g of ethyl 2-[(2-chloro-1-oxo-3-methylbutyl)-amino]-β-oxo-α-[(2-thiazolylamino)-carbonyl]-3-trifluoromethyl-benzene-propanoate melting at 160° C. A second lot of 8.2 g of the said product was obtained afterwards melting at 160° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:15][CH:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>C(#N)C>[CH3:15][CH:16]1[CH:21]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=2)[CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1
Reactant: CC1CNCC(C)C1
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Solvent: CC#N
Product: CC1CNCC(C)C1c1ccc([N+](=O)[O-])c2ccccc12

Procedure:
A Pyrex tube was charged with 1-chloro-4-nitronaphthalene (52 mg, 0.25 mmol) and 3,5-dimethylpiperidine (133 μL, 1.0 mmol) followed by acetonitrile (2 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180° C., 5 min). The reaction mixture was filtered and the solid washed with cold ethanol. If needed the compound was purified according to Purification method C. Yield: 58 mg (82%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[CH:5]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O.Cl>[CH3:13][C:6]1[CH:5]=[C:4]([C:3]2[CH:17]=[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc(/C(Cl)=N/O)ccc1[N+](=O)[O-]
Reactant: C#CC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(C)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of (Z)—N-hydroxy-3-methyl-4-nitrobenzimidoyl chloride (1.0 equiv.), ethyl propiolate (2.0 equiv.) in toluene was dropwise added Et3N over a period of 30 min. at RT and continued stirring at RT for 15 min. The reaction mixture was then heated at 80° C. for 16 hours. Reaction mass was diluted with EtOAc and neutralized with dilute HCl. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 100% CHCl3, to provide the title compound as creamish crystals (65%); 1H NMR (300 MHz, DMSO-d6) δ: 1.31-1.36 (t, J=7.0 Hz, 3H), 2.56 (s, 3H), 4.35-4.42 (q, 2H), 7.99-8.02 (m, 2H), 8.08 (s, 1H), 8.11 (m, 1H); IR (KBr) 3124, 3091, 2995, 2908, 1727, 1612, 1588, 1520, 1443, 1344, 1285, 1140, 1015, 950, 873, 771 cm−1.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1.[N:19]1[CH:20]=[C:21]2[N:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=13)[S:24][C:23]([C:31](O)=[O:32])=[CH:22]2.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[OH-].[Na+]>O.O1CCCC1.C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[C:13]1([CH2:12][CH2:11][CH2:10][N:7]2[CH2:8][CH2:9][CH:4]([NH:3][C:31]([C:23]3[S:24][C:25]4[N:30]5[C:21](=[CH:20][N:19]=[C:29]5[CH:28]=[CH:27][CH:26]=4)[CH:22]=3)=[O:32])[CH2:5][CH2:6]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NC1CCN(CCCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
Triethylamine (6.7 ml) was added dropwise to a suspension of 4-amino-1-(3-phenylpropyl)piperidine dihydrochloride (7.01 g) and dimethylformamide (40 ml). The mixture was stirred for 10 minutes. 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (5.00 g), 1-hydroxy-1H-benzotriazole monohydrate (0.710 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (4.61 g) were added into the reaction mixture. This was stirred for 2 hours at 68-70° C. (inner temperature). Ethyl acetate:tetrahydrofuran=4:1 (380 ml), 1N-sodium hydroxide (50 ml) and water (80 ml) were added into the reaction solution. The aqueous layer was extracted by ethyl acetate:tetrahydrofuran=4:1 (120 ml×2). The organic layer was washed with water (130 ml×3), and then concentrated. The residue which was added ethyl acetate (15 ml) was stirred for 2 hours at room temperature. The reaction mixture was dried under reduced pressure to obtain N-[1-(3-phenylpropan-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (8.87 g, 92.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][C:26]3[CH:29]=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:31][C:25]=3[C:24]2=[O:39])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CNCCNC>C(Cl)Cl.[Cu]I.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH:14][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:28]=[CH:27][C:26]4[CH:29]=[C:30]([C:32]5[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=5)[S:31][C:25]=4[C:24]3=[O:39])=[CH:21][CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)C1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2)C1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
Combine 3-carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.96 mmol), 6-(4-bromo-phenyl)-2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (0.2 g, 0.48 mmol), Cs2CO3 (0.31 g, 0.96 mmol), 1,4-dioxane (5 mL), and CuI (0.037 g, 0.19 mmol). Purge the mixture with nitrogen for 10 min and then add sym-dimethylethylene diamine (0.034 g, 0.38 mmol). Heat the mixture at 100° C. overnight. Cool the mixture to RT, dilute with CH2Cl2, and wash twice with a solution of 5% NH4OH/H2O. Dry the organic layer over Na2SO4, filter, and concentrate. Filter the crude with Et2O and water to give 0.117 g (43%) of the title compound. LC-ES/MS m/z (35Cl) 494.0 [M−tert Bu+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[Mg]Br>>[F:16][C:2]([F:15])([F:1])[C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5]([OH:14])([C:19]1[CH:18]=[CH:17][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=1)[C:6](=[O:13])[NH:7]2
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O
Product: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1(O)c1ccc2ccccc2c1
Yield: 6.5 %

Procedure:
The title compound (35.8 mg, 6.5%) was prepared from 4-trifluoromethyl-6-iodoisatin (400 mg, 1.17 mmol) and 2-naphthyl magnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:53][C:54]1[CH:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:60]([C:57]3[CH:56]=[CH:55][C:54]([Cl:53])=[CH:59][N:58]=3)=[O:61])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cn3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 91.5 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 14 (b)) in THF (4 ml) were added sequentially N-methylmorpholine (0.21 ml), TBTU (301 mg) and 5-chloro-2-pyridinecarboxylic acid (111 mg, CAS 86873-60-1) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (197 mg, 91%) as a white solid. MS (ISP): 484.3 ([{37Cl}M+Na]+), 482.3 ([{35Cl}M+Na]+), 462.4 ([{37Cl}M+H]+), 460.5 ([{35Cl}M+H]+), 406.4 ([{37Cl}M+H—C4H8]+), 404.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14]CC)=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].N1C=CC=CC=1>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Solvent: c1ccncc1
Product: CC(=O)c1cc2c(cc1O)OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 1.1 g sample of racemic ethyl 7-hydroxychroman-2-carboxylate was treated with 10 ml of 1:1 acetic anhydride - pyridine and stirred for 17 hours at room temperature. After removal of the solvents, the residual product (1.2 g) was dissolved in 12 ml of glacial acetic acid and treated with 1.26 ml of borontrifluoride etherate. The reaction mixture was gently refluxed for 17 hours, cooled, poured carefully into a mixture of sodium bicarbonate and ice and the product extracted with 1:1 tetrahydrofuran-ether. After evaporation of the solvent, 1.1 g of crude racemic-7-hydroxy-6-acetylchroman-2-carboxylic acid was obtained. Conversion of this material into the corresponding ethyl ester was achieved by refluxing 1.1 g of the crude acid in absolute ethanol in the presence of 10 mg of p-toluenesulfonic acid for 17 hours. After removal of most of the solvent, the product was extracted with 1:1 tetrahydrofuran-ether, washed with saturated sodium bicarbonate solution, water, dried and the solvents concentrated to give 1.2 g of crude ethyl ester as a mixture of the 6-acetyl and 8-acetyl derivatives in a ratio of about 7:1. This material was purified by column chromatography on silica gel to afford 0.7 g (53.5%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester as a colorless crystalline material mp 93.5°-95.5° C. (from ethyl acetate-hexane).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccn3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccccn3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (30 mg, 0.07 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (14 mg, 0.33 mmol) in water (1 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (20 mg, 69%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H), 8.84 (d, J=3.9 Hz, 1H) 8.12-8.20 (m, 1H) 7.85-8.02 (m, 3H) 7.76 (dd, J=7.6, 4.6 Hz, 1H) 7.69 (s, 1H) 7.39 (t, J=8.6 Hz, 1H) 7.33 (s, 1H) 3.91 (d, J=11.7 Hz, 2H) 3.72 (s, 2H) 2.99 (t, J=11.7 Hz, 3H) 1.89 (d, J=12.7 Hz, 2H) 1.63-1.78 (m, 2H); MS cald. for C22H22FN2O4S [(M+H)+]: 429, obsd. 429.2.
Reaction SMILES: [Cl:1][C:2](Cl)([P:13](=[O:22])([O:18][CH:19]([CH3:21])[CH3:20])[O:14][CH:15]([CH3:17])[CH3:16])[P:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([CH3:7])[CH3:6].S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][CH:2]([P:3](=[O:12])([O:4][CH:5]([CH3:7])[CH3:6])[O:8][CH:9]([CH3:11])[CH3:10])[P:13](=[O:22])([O:18][CH:19]([CH3:20])[CH3:21])[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)OP(=O)(OC(C)C)C(Cl)(Cl)P(=O)(OC(C)C)OC(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)OP(=O)(OC(C)C)C(Cl)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.25 h

Procedure:
Into a solution containing 8.2 g (0.02 moles) of tetraisopropyl (dichloromethylene)bisphosphonate in 70 ml of ethanol, 9.0 g of sodium sulphite in 250 ml of water are added while stirring during 15 minutes at 10° to 15° C., whereafter the mixture is stirred for 1 h. The mixture is extracted with chloroform and the extract is dried (MgSO4) and filtered. The filtrate is evaporated under a vacuum, whereby about 7.6 g (100% of the theor.) of tetraisopropyl (monochloromethylene)bisphosphonate (31P-NMR (CDCl3 : δ 12.04 ppm) are obtained as a colourless oil, at a concentration of 98%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21]C)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.B(Br)(Br)Br>>[Cl:1][CH2:2][C:3]1[C:4]([CH2:19][CH2:20][OH:21])=[N:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: BrB(Br)Br
Product: OCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl

Procedure:
In analogy to the procedures described in examples 103A], 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine and BBr3 (1M in dichloromethane) gave the title compound as a yellow oil, which was used without further purification. MS: 317.1 (M+H, Cl)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:20](=O)[CH:21]([CH3:23])[CH3:22])=[N:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[CH:21]([C:20]1[N:16]2[CH:17]=[C:12]([C:11]3[O:10][CH:9]=[N:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:13]=[CH:14][C:15]2=[N:18][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)c1nnc2ccc(-c3ocnc3-c3ccccc3)cn12
Temperature: 75 °C
Yield: 42.7 %

Procedure:
Isobutyric acid N′-[5-(4-phenyl-oxazol-5-yl)-pyridin-2-yl]-hydrazide (730 mg, 2.26 mmol) was taken up in phosphorous oxychloride (10 mL) and heated at 75° C. for 18 hours. The reaction was cooled with an ice bath, added to a beaker of water (50 mL), and the mixture was made basic by dropwise addition with 3 N sodium hydroxide. The basic mixture was extracted with ethyl acetate (3×); the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to a yellow oil. The residue was recrystallized from ethyl acetate/methanol (95/5) affording the title compound as yellow crystals (294 mg, 43%). The filtrate was purified by flash chromatography (eluting with ethyl acetate/methanol 97:3) to give more of the title compound (220 mg, 32%). LCMS (m/z) 305 M+1. 1H NMR (400 MHz, CDCl3) δ8.22 (s 1 H), 8.05 (s, 1 H), 7.84 (d, 1 H, J=9.8 Hz), 7.64-7.66 (m, 2 H), 7.44 7.49 (m, 4 H), 3.29-3.34 (m, 1 H), 1.51 (d, 6 H, J=7.2 Hz).