Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1)(=[O:24])=[O:23]
Reactant: O=C1NC(CO)Cc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1Cc2ccccc2C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Dissolve 3-(hydroxymethyl)-3,4-dihydro-2H-isoquinolin-1-one (6.0 g, 33.86 mmol) in DCM (60 mL) and add triethylamine (7.25 g, 67.72 mmol). Cool to 0° C. and add methanesulfonyl chloride (4.65 g, 40.63 mmol) drop-wise. Stir for one hour; dilute with DCM; and wash with water and then brine. Remove the solvents under reduced pressure to give the title compound (8.0 g, 92%). MS (m/z): 256 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[C:47]([O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:49])[CH3:48].C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:54]2[CH2:55][CH2:56][CH:51]([O:50][C:47](=[O:49])[CH3:48])[CH2:52][CH2:53]2)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:11])[CH3:12])\[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(=O)OC1CCNCC1
Reactant: COC(=O)/C(Cc1ccc(C(=O)O)cc1)=C(\C(=O)OC)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C(Cc1ccc(C(=O)N2CCC(OC(C)=O)CC2)cc1)=C(\C(=O)OC)C(C)C
Yield: 77.4 %

Procedure:
To a solution of 2-(4-carboxybenzyl)-3-isopropylmaleic acid dimethyl ester (10.3 mg, 0.0322 mmol) in dichloromethane (500 μL) were added 1-hydroxybenzotriazole (13.3 mg, 0.0965 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.8 mg, 0.109 mol), piperidin-4-yl acetate hydrochloride (28.8 mg, 0.161 mmol) and triethylamine (14.6 mg, 0.145 mmol) with stirring under ice cooling. After stirring at room temperature for 1 h, the reaction mixture was diluted with water to separate the phases. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate1:2) to give 11.1 mg of the title compound as a solid (yield: 78%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH2:36][NH2:37])[CH3:30]>O1CCCC1.ClCCl>[CH2:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH2:36][NH:37][C:4](=[O:6])[C:3]1[C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=[C:10]([Br:11])[C:2]=1[NH2:1])[CH3:30]
Reactant: COc1cc(Br)c(N)c(C(=O)O)c1OC
Reactant: CCN1CCC[C@H]1CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCC[C@H]1CNC(=O)c1c(N)c(Br)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 2-amino-3-bromo-5,6-dimethoxybenzoic acid (0.96 g, 3 mmol) and triethylamine (0.58 ml, 4.2 mmol) in 15 ml tetrahydrofuran/ /dichloromethane (1:1) was added ethyl chloroformate (0.32 ml, 3.4 mmol) at -20° C. After stirring for 45 min. at -20° C. a solution of (2S)-(-)-1-ethyl-2-aminomethylpyrrolidine in 10 ml dichloromethane was added at -20° C. After stirring for 3 h at room temperature the mixture was washed with water and extracted with 0.5M HCl. The aqueous phase was made alkaline and extracted twice with dichloromethane. Drying (Na2SO4) and evaporation gave 0.45 g crude material which was purified by chromatography on a C18 reversed phase column with H2O/MeOH/NH3 40:60:0.3 as eluent to give 0.25 g (22%) pure product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: O=c1c2c(CCc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reaction time: 3.5 h
Yield: 92.6 %

Procedure:
To a solution of 3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (131 mg, 0.32 mmol, prepared in Example 11) in DMF (4 ml) and methanol (4 ml) was added activated carbon-palladium (13 mg), and the mixture was stirred under hydrogen atmosphere for 3.5 hours, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (113 mg, 93%).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([C:24]2(Cl)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][C:24]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:9]([OH:10])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Solvent: c1ccncc1
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4Oc4ccccc43)O2)cc1I
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Iodo-2'-deoxyuridine (IDU) (3.54 g, 10 mmol) was coevaporated with dry pyridine (3×20 mL). The IDU was redissolved in dry pyridine (15mL) and 9-phenyl-9-chloroxanthen (3.82 g, 13 mmol) was added to the stirring solution in two equal portions over 0.5 h. After 1h, MeOH (5 mL) was added and the solution stirred for a further 0.5 h. The solvent was then removed under vacuum, and the residue recrystallized from a 1% Et2N/ethyl acetate solution giving 7 as colourless crystals (4.27 g, 70%), mp 200-2° C. 1H NMR (d6 -DMSO): δ2.20 (m, 2H, H2'), 2.99 (dd, 1H, H5', J-10.5, 4.2 Hz), 3.10 (dd, 1H, H5", J=10.5, 2.7 Hz), 3.85 (m, 1H, H4'), 4.15 (m, 1H, H3'), 5.29 (d, 1H, 3'OH, J=4.2 Hz), 6.08 (t, 1H, H1', J=7.0 Hz), 7.10-7.42 (m, 13H, Px CH), 8.08 (s, 1H, H6). 13C NMR (d6 -DMSO): δ40.4 (C2'), 63.8 (C5'), 69.9 (C5), 71.0 (C3'), 75.6 (Px C9), 85.2 (Cl'), 85.9 (C4'), 116.3, 116.4 (Px CH), 122.3, 122.4 (Px C8a and C9a), 123.8, 124.0, 125.8, 126.8, 128.2, 129.3, 129.69, 129.7, 129.73 (Px CH), 143.9 (C6), 148.4(Px Cl'), 150.0 (C2), 150.51, 150.58 (Px C4a and C10a), 160.6 (C4). FABMS m/z 633 (M+Na'). Anal. calcd for C28H23N2P6I: C, 55.1; H,3.81, N, 4.59. Found: C, 55.0; H, 3.81, N, 4.54.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH:8]([CH3:12])[C:9](=O)[CH3:10]>>[ClH:7].[CH3:1][N:2]1[C:9]([CH3:10])=[C:8]([CH3:12])[S:6][C:3]1=[N:4][NH2:5]
Reactant: CNC(=S)NN
Reactant: CC(=O)C(C)Cl
Product: Cc1sc(=NN)n(C)c1C
Product: Cl

Procedure:
From 4-methyl-3-thiosemicarbazide and 3-chloro-2-butanone.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(OC([O:15][C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH2:22]Cl)=[CH:18][C:17]=1[O:26][CH3:27])=O)C.O>C1C=CC=CC=1.[OH-].[K+].CO>[OH:15][C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH2:22][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[CH:18][C:17]=1[O:26][CH3:27]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Oc1ccc(C=CCCl)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COc1cc(C=CCN2Cc3ccccc3C2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
The process for preparing this compound will be described below, along with its physical properties. A solution of 5.6 grams of isoindoline in 50 milliliters of benzene is added dropwise to a solution of 4.7 grams of 4-ethoxycarbonyloxy-3-methoxy-cinnamyl chloride in 30 milliliters of benzene, after which the mixture is stirred for 1 hour at room temperature and then for 2 hours at 60° C. After completion of the reaction, water is added to the reaction mixture and extracted with benzene followed by distilling the solvent off to obtain an oily product, which is dissolved in a solution of 0.95 gram of potassium hydroxide in 50 milliliters of methanol and stirred for 30 minutes at room temperature. The reaction solution is then concentrated to dryness, and a 5% aqueous sodium hydroxide solution is added to the residue to precipitate crystals, which are filtered off. After adding an excess of ammonium chloride to the mother liquor, it is extracted with chloroform. The oily product obtained after distilling off the chloroform is transformed to a maleic acid salt by operating as in Example 15, which then is recrystallized from methanol to obtain 3.5 grams (yield 56.8%) of N-(4-hydroxy-3-methoxycinnamyl)-isoindoline.maleic acid salt as crystals having a melting point of 162°-164° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[CH3:32][C@@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34]1>CN(C=O)C.N1C=CC=CC=1>[CH3:32][C@@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]1[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Reactant: C[C@@H]1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=S)n1C

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 126 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30]C(=C)[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C[N+]1([O-])CC[O:36]CC1.[O-]S([O-])=O.[Na+].[Na+].CCO[C:49]([CH3:51])=[O:50]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:51]([CH2:49][OH:50])([OH:36])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: CCOC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: OCC1(O)CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[8-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline (0.26 mmol, 110 mg) was dissolved in 8 mL solution (THF:H2O=3:1) and charged with NMO (0.52 mmol, 0.18 mL, 50% aq. solution) and K2OsO4.H2O (0.26 mmol, 9.6 mg). The resulting mixture was stirred at rt overnight. The reaction was quenched with Na2SO3 (1.30 mmol, 164 mg), diluted with EtOAc (40 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the desired product as a yellow solid; MS (ES+): m/z 457/396 (10/1) [MH+].
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:16]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1)(=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To 300 mL of CH2Cl2 was added 3-nitrophenol (structure 64 of Scheme XVII, where R1 =H, Y=O) (15 g, 0.11 mol), pyridine (20 mL) and DMAP (10 mg). To this cooled solution (0° C.) was slowly added trimethylacetyl chloride (18 mL, 146 mmol, 1.4 equivuiv). The solution was allowed to warm to rt and stirred for 3 h. To the amber colored solution was added sat'd NH4Cl (300 mL). The organic layer was washed with 1N HCl (2×150 mL), 10% CuSO4.5 H2O (2×100 mL), and brine (2×100 mL). The extract was dried (Na2SO4) and concentrated in vacuo to give 22.5 g (94%) of O-pivaloyl-3-nitrophenol as a white solid. Data for O-pivaloyl-3-nitrophenol: Rf 0.55 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 8.11 (dd, J=4.2, 1.3, 1 H), 7.96 (t, J=2.2, 1 H), 7.56 (dd, J=8.4, 8.2, 1 H), 7.42 (dd, J=6.5, 1.3, 1 H), 1.35 (s, 9 H).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCN1C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.22 g) in methanol (20 ml) was added 28% sodium methoxide in methanol solution (0.61 ml) on ice-bath under atmospheric pressure of nitrogen and the mixture was stirred at the same condition for 30 minutes. To a reaction mixture was added acetic acid (0.17 ml) and evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 ml) and the solution was washed twice with saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.76 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=CC=CC=1.O=CCCC[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:29]([O:28][C:27]([NH:26][CH2:7][CH2:2][CH2:1][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCC=O
Reactant: COC(=O)CCCN1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCN1CCN(CCCNC(=O)OC(C)(C)C)CC1
Reaction time: 20 h
Yield: 78.2 %

Procedure:
To a solution of methyl 4-(4-benzylpiperazin-1-yl)butanoate (500 mg, 2.68 mmoles) in dichloromethane (5 mL) was added tert-butyl 4-oxobutyl-carbamate (505 mg, 2.68 mmoles) and sodium triacetoxyborohydride (900 mg, 1.5 eq) and stirred 20 h. To the reaction mixture water was added followed by 1M aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate. The organics were evaporated to afford methyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propyl}-piperazin-1-yl)butanoate (0.72 g, 75%). MS (ESI+) for m/z 358 (M+H)+.
Reaction SMILES: [C:1](=[O:21])([O:11]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:31]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH:1]([OH:11])=[O:2].[C:31]1([N:37]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(COC(=O)N2CCN(c3ccccc3)CC2)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.9 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 5.70 g, 19.4 mmol) was dissolved in DMF (40 mL). DIPEA (6.75 mL, 38.7 mmol) and 1-phenyl-piperazine (2.96 mL, 19.4 mmol) were added. The reaction mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and washed sequentially with sat aq NaHCO3 solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 98:1:1 mixture of DCM:MeOH:DIPEA) followed by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-80%) to give (1-methylpiperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate formate (0.63 g, 10.3%) as a viscous yellow oil.
Reaction SMILES: C([OH:3])C.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:21](Cl)=[O:22])[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C[C:25]1[CH:30]=CC=CC=1>>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:21]([O:22][CH2:30][CH3:25])=[O:3])[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Reactant: CCO
Product: CCOC(=O)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To 120 parts of absolute ethanol is added dropwise a solution of 102 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane-8-carbonyl chloride in 270 parts of methylbenzene, while cooling. Upon completion, the whole is stirred for 24 hours at reflux temperature. The reaction mixture is cooled, washed with water, dried, filtered and evaporated, yielding 95 parts (90.6%) of ethyl 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane-8-carboxylate as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:39][C:40]1[S:41][C:42]2[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:43]=2[N:44]=1>>[F:49][C:47]1[CH:46]=[CH:45][C:43]2[N:44]=[C:40]([NH:39][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[N:22][C:14]=3[NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[S:41][C:42]=2[CH:48]=1
Reactant: COc1cc(Nc2ncccc2C(=O)O)cc(OC)c1OC
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncccc2C(=O)Nc2nc3ccc(F)cc3s2)cc(OC)c1OC
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and 3,4,5-methoxy aniline (20, 183 mg, 1 mmol) was taken in ethylene glycol and refluxed at 160° C. for 6 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain Ethyl 2-(3,4,5-trimethoxy anilino) nicotinate (27) as pure product. Ethyl2-(3,4,5-trimethoxy anilino) nicotinate (27, 332 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(3,4,5-trimethoxyphenylamino) nicotinic acid (34). To a stirred solution of 2-(3,4,5-trimethoxyphenylamino) nicotinic acid (34, 244 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-fluoro benzothiazole (36, 117 mg, 0.7 mmol) were added Then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (11) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1.Cl.[O:13]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[CH:25]=[C:26]4[NH:32][C:31]([NH:33][C:34](=[O:37])[O:35][CH3:36])=[N:30][C:27]4=[N:28][CH:29]=3)=[CH:23][C:18]=2[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:16]2[CH2:17][C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]5[NH:32][C:31]([NH:33][C:34](=[O:37])[O:35][CH3:36])=[N:30][C:27]5=[N:28][CH:29]=4)[CH:21]=[CH:20][C:19]=3[O:13][CH2:14][CH2:15]2)=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reactant: O=C(Cl)N1CCC(CF)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A mixture of 4-(fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (24 mg, 0.13 mmol), methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (34 mg, 0.091 mmol), and diisoproylethylamine (59 mg, 0.45 mmol) in dichloromethane (0.5 mL) and N,N-dimethylformamide (0.5 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated then dissolved in methanol (2 mL) and purified directly by preparative reverse phase HPLC to give methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate, (21 mg, 48% yield), (400 MHz, DMSO-d6): 8.41 (br, 1H), 7.87 (s, 1H), 7.54 to 7.44 (m, 2H), 7.05 (d, 1H), 4.45 (s, 2H), 4.31 (dd, 2H), 4.19 (m, 2H), 3.67 to 3.55 (m, 4H), 2.74 (t, 2H), 1.84 (br, 1H), 1.67 to 1.58 (m, 2H), 1.29 to 1.18 (m, 2H); MS (EI) for C24H27FN6O4: 483 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[NH:14][C:13]2=[O:20])=[C:4]([F:21])[CH:3]=1.[H-].[Na+].Cl[CH:25]([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:25]([F:27])[F:26])[C:13]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Reaction time: 0.5 h

Procedure:
A solution of 2.00 g of 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -methyl-2,4(1H,3H)-pyrimidinedione in 20 ml dimethylformamide is added dropwise at room temperature while stirring within 30 minutes to a suspension of 0.28 g of a 55% sodium hydride dispersion in 10 ml of dimethylformamide. The mixture is subsequently stirred for 30 minutes and thereafter 5.26 g of chlorodifluoromethane are introduced at 55° C. while stirring during 18 hours. The reaction mixture is cooled, poured into a solution of 20 ml of 2N hydrochloric acid in 300 ml of water and extracted with 150 ml of ethyl acetate. The organic phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of diethyl ether and the solution is treated with active carbon and filtered. The filtrate is evaporated to dryness and the residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-difluoromethyl-6 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 97°-99° C.