Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:20][C:4]1[N:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1nc(-c2ccc(Cl)c(Cl)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 11.6 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,4-dichlorophenylboronic acid (116 mg, 0.61 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 110 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (30 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 20 g, 18-32%, gradient 2.5-20% ethanol in DCM, residue dry loaded) and twice by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 48% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 50% acetonitrile) afforded (2R,3R,4S,5R)-2-{6-amino-2-(3,4-dichlorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 9 as a white solid (24.4 mg, 11%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]([CH3:12])[CH2:9][O:10][CH3:11])=[O:6].[H-].[Na+].CCOC(C)=O.O>C1COCC1>[CH3:11][O:10][CH2:9][C@@H:8]([N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[CH3:12]
Reactant: COC[C@H](C)NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A −20° C. solution of (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (1.092 g, 5.61 mmol) in THF (25 mL) was treated portion-wise with NaH (60% in mineral oil, 505 mg, 12.62 mmol), allowed to warm to RT and stirred overnight. The mixture was treated with EtOAc, water, then 5% citric acid, the layers separated and the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford (S)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (95 mg, 11%). MS (ESI) m/z: 159.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)Cl.CN(C)C.Cl[C:24]([O:26][CH2:27][C:28]#[CH:29])=[O:25]>C(Cl)Cl.O>[CH2:27]([O:26][C:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:24]([O:26][CH2:27][C:28]#[CH:29])=[O:25])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)=[O:25])[C:28]#[CH:29]
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: C#CCOC(=O)Cl
Agent: CN(C)C
Solvent: ClCCl
Solvent: O
Product: C#CCOC(=O)Oc1ccc(Cc2ccc(OC(=O)OCC#C)cc2)cc1
Yield: 93.6 %

Procedure:
A flask equipped with a stirrer, thermometer, nitrogen gas tube and reflux condenser was charged with 20.0 g of bis(4-hydroxyphenyl)methane, 50.0 g of methylene chloride and 23.0 g of trimethylamine. To the flask was added 26.0 g of propargyl chloroformate dropwise over one hour and the mixture was allowed to react for 6 hours at 30° C. After the reaction, the reaction mixture was treated with methylene chloride-water mixture and the organic phase was separated followed by drying over magnesium sulfate overnight. After filtering, the filtrate was evaporated in a rotary evaporator. The resulting crystals were recrystallized to give the title compound melting at 60° C. at a yield of 93.6% of theory.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(I)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO4 and evaporated in vacuo to afford 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63° C.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:11]=1)#[N:2].[C:22]1([C@H:28]([NH2:31])[CH2:29][CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1.C>C(O)(C)C>[C:1]([N:3]=[C:4]([NH:31][C@@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:29][CH3:30])[NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=1)#[N:2]
Reactant: CC[C@@H](N)c1ccccc1
Reactant: CN(C)c1ccc(NC(=NC#N)Oc2ccccc2)cn1
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: CC[C@@H](NC(=NC#N)Nc1ccc(N(C)C)nc1)c1ccccc1
Yield: 5.2 %

Procedure:
A stirred solution of the product from Step 4 (2.00 g, 0.00711 mol), (R)-(+)-1-phenylpropylamine (1.06 g, 0.00784 mol), N-methylmorpholine (1.69 ml, 0.0154 mol) and isopropanol (13.3 ml) was refluxed, under nitrogen, until the reaction was shown to be complete by TLC (28 hours). It was then concentrated and the residue chromatographed on silica gel with 1 to 4% MeOH-CHCl3. A solution of the product thus obtained in MeOH-EtOAc was decolorized with Darco (activated charcoal) and crystallized from EtOAc-hexane to give 1.02 g, m.p. 109°-111° C. and 0.120 g, m.p. 107°-113° C. of the titled product.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CC2)nn1
Yield: 82 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (85 mg, 82%) which was obtained as a light brown solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][C@H:2]([C:7]([O:9][CH3:14])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCSC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of methionine (30.0 g, 201 mmol) in methanol (500 mL) was added dropwise thionyl chloride (36 g, 0.30 mol) at 0° C. The reaction mixture was heated to 80° C. After 2 hours, the reaction mixture was concentrated under reduced pressure to give methyl methioninate. The material was used without purification. MS ESI calc'd. for C6H14NO2S [M+H]+ 164. found 164. 1H NMR (300 MHz, CD3OD) δ 4.19 (t, J=6.6 Hz, 1H), 3.84 (s, 3H), 2.64 (t, J=6.6 Hz, 2H), 2.24-2.12 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1.[CH3:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:4]2([CH2:3][CH2:2][N:19]([CH3:20])[CH3:18])[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C2(CCCl)C=CCCC2)c1
Reactant: CNC
Solvent: Cc1ccccc1
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Reaction time: 5 h

Procedure:
1 g of 1-[1-(2-chloroethyl)-2-cyclohexen-1-yl]-3-methoxybenzene is dissolved in 10 ml of toluene, and the solution is treated with 10 ml of dimethylamine. The mixture is held at 150° C. for 5 hours in a bomb tube. After evaporation of the solvent, the residue is treated with 3 N hydrochloric acid. The aqueous phase is extracted with ether and made alkaline with an excess of ammonia, whereupon the precipitated rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. The hydrochloride of this compound melts at 161°-162° C.
Reaction SMILES: [C:1]1([CH:7]([SeH])[CH:8]([CH2:15]C)[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([C:8](=[CH2:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH3:1]
Reactant: CCC(CCC(=O)OC)C([SeH])c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CC)CCC(=O)OC
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of selenide XIII (1.8 g, 6.0 mmol) in methylene chloride (15 ml) at -78° C. was added m-chloroperbenzoic acid (1.28 g, 85%, 6.3 mmol). The solution was allowed to warm to room temperature over 30 min. and was then washed with water, saturated sodium carbonate and dried (MgSO4). The methylene chloride was removed in vacuo and the selenoxide was taken up in carbon tetrachloride (15 ml). Triethylamine (640 mg, 6.3 mmol) was added and the solution was refluxed under nitrogen for 2 h. The reaction was taken up in methylene chloride (25 ml), washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated on a roto-evaporator. The crude olefin XIV was distilled bp 70°-75° C. (25 mm) to give a colorless oil (630 mg, 74%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][C@@H:10]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:14][CH2:13][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1.[OH-].[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:23]([N:12]1[CH2:13][CH2:14][C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C@@H:10]([CH2:9][NH:8][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CN
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CNS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
39 μL of triethylamine and 18 μL of dimethylsulfamoyl chloride were added to chloroform (1 mL) solution of 41 mg of (3S*,4S*)-3-aminomethyl-1-benzyl-4-o-tolyl-piperidine obtained in Production Example 37, and stirred at room temperature for 2.5 hours. 39 μL of triethylamine and 18 μL of dimethylsulfamoyl chloride were further added to the reaction liquid, and stirred at room temperature for 1 hour. Still further, 39 μL of triethylamine and 18 μL of dimethylsulfamoyl chloride were added to the reaction liquid, and stirred at room temperature for 1 hour. Aqueous 1 M sodium hydroxide solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 27 mg of the entitled compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH2:12].[C:13](O)([C:15]([F:18])([F:17])[F:16])=O>>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:3][C:4]=2[CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Product: COc1ccc2[nH]c(C(F)(F)F)nc2c1

Procedure:
Synthesized as described Example 195C from [2-amino-4-(methyloxy)phenyl]amine dihydrochloride and TFA: MS (ESI) m/z 217 (M+1).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>O1CCCC1>[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1
Reactant: Nc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cn[nH]c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
3-(1-Trityl-1H-pyrazol-4-yl)-pyridin-2-ylamine (2.3 g, 5.71 mmol) described in Manufacturing Example 32-1-3, 2 N hydrochloric acid (15 mL), methanol (15 mL) and tetrahydrofuran (10 mL) were stirred for 30 minutes at 70° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. Saturated sodium bicarbonate solution was added to the separated aqueous layer, which was then extracted with ethyl acetate 6 times. The ethyl acetate layers were combined and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=10:1) to obtain the title compound (625 mg, 68.3%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)=O>O>[C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:3])=[O:25])=[CH:26][CH:27]=1)(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(C)=O
Reactant: C/C=C/C(=O)Oc1ccc(C=O)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C/C=C/C(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of Jones' reagent were added dropwise while stirring within 15 minutes to a solution of 12.2 g of 4-[(E)-but-2-enoyloxy]benzaldehyde and 100 ml of acetone at 0° C. The reaction mixture was stirred at room temperature overnight, poured into water and extracted three times with 50 ml of ethyl acetate each time. The combined organic phases were extracted twice with 50 ml of 2N sodium hydroxide solution. The combined sodium hydroxide phases were acidified (pH 1) with hydrochloric acid, then extracted three times with SO ml of ethyl acetate. The organic phases were combined and washed twice with 50 ml of water, dried over magnesium sulphate, filtered and subsequently concentrated. Recrystallization of the residue from ethanol gave 10.5 g of 4-[(E)-but-2-enoyloxy]benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH3:27])[CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:28].B(Cl)(Cl)Cl.ClCCl.C(=O)(O)[O-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.O>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:27])[CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:28]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A mixture of 8-fluoro-5-[(4-methoxy-3-methylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.30 g, 0.75 mmol) and tetrabutylammonium iodide (0.69 g, 1.9 mmol) was treated with 1 M boron trichloride in dichloromethane (1.9 mL, 1.9 mmol) at room temperature. After stirring for 24 hours at room temperature, the mixture was treated sequentially with water (20 mL), a saturated, aqueous, sodium bicarbonate solution (50 mL), and ether (20 mL). The separated aqueous phase was extracted with diethyl ether (3×25 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a residue. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4 to 3:7 gradient) to yield, the title compound as a homogeneous solid (0.21 g, 73%), m.p. 196° C.;
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[C:6](C2C=CC=CC=2)=[C:7]([C:14]([C:16]2[CH:17]=[CH:18][C:19]3[N:24]=C(C4C=CC=CC=4)[O:22][C:21](=[O:31])[C:20]=3[CH:32]=2)=[O:15])[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2.Cl>O.CN1CCCC1=O>[NH2:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]([C:7]2[N:8]3[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]3)=[C:5]([O:4][CH3:3])[CH:6]=2)=[O:15])=[CH:32][C:20]=1[C:21]([OH:31])=[O:22]
Reactant: COc1c(-c2ccccc2)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Temperature: 80 °C
Yield: 105.6 %

Procedure:
1.56 g (27.94 mmol) of potassium hydroxide dissolved in 4 ml of water are added, at ambient temperature, to 4.4 g (9.31 mmol) of 6-[(1-methoxy-2-phenylindolizin-3-yl)carbonyl]-2-phenyl-4H-3,1-benzoxazin-4-one in 50 ml of N-methylpyrrolidone. The reaction medium is heated at 80° C. for 24 hours. The reaction medium is poured into a 1N aqueous solution of hydrochloric acid. The precipitate formed is filtered off and rinsed with water. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 3.05 g of a green solid are obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C([BH3-])#N.[Na+].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH:32]=O.C[O-].[Na+].CO.C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:32][NH:2][CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:7][CH2:8]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: Cc1ccc(C=O)cc1F
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4ccc(C)c(F)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.22 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 7 mL of methanol, 66 mg of sodium cyanoborohydride, 64 μL of 3-fluoro-4-methylbenzaldehyde, 0.30 g of a 28% sodium methoxide/methanol solution and 30 μL of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. Thereto was added 22 mg of 3-fluoro-4-methylbenzaldehyde, and the mixture was stirred at the same temperature for 1 hour. Thereto was further added 33 mg of sodium cyanoborohydride, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and the solvent was distilled off under reduced pressure. Thereto was added chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=9:1 to obtain 20 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a colorless oily substance.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)[C:22]([C:37]#[N:38])=[C:21](SC2C=CC=CC=2)[N:20]=1.Cl>COCCOC.O>[NH2:18][C:19]1[N:20]=[C:21]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[C:22]([C:37]#[N:38])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cccc(CO)c1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(N)nc(OCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.65 g (14.68 mmol) of potassium tert-butoxide were suspended in 15 ml of 1,2-dimethoxyethane. After addition of 0.97 g (5.87 mmol) of 3-(hydroxymethyl)benzenecarboxylic acid (Example 66A) and 1.14 g (2.94 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 35A), the mixture was stirred at 60° C. overnight. After cooling of the reaction mixture, 50 ml of water were added. With ice-cooling, the clear solution was acidified to pH 1 using conc. hydrochloric acid. The aqueous phase was decanted from the viscous precipitate formed. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). The aqueous phase was evaporated and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7][C:8](=[O:12])O[C:10](=[O:11])[C:5]=2[CH:4]=1.[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][NH:20][CH2:21]C(O)=O>CC1C=CC(C)=CC=1>[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][N:20]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([S:2][CH3:1])[CH:14]=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:21]1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Reactant: CSc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(SC)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-methylsulfanyl-1H-benzo[d][1,3]oxazine-2,4-dione (4.8 g, 23 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (5.6 g, 25 mmol) in p-xylene (50 mL) was heated under reflux (150° C.) for 3 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2×20 ml). Yield: 7.5 g (89%). m/z 373 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12]O)[CH:4]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:21]>>[Cl:21][CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: COc1cc(CO)cc2c1OCO2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(CCl)cc2c1OCO2
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of SOCl2 (150 mL) was added (7-methoxybenzo[d][1,3]dioxol-5-yl)methanol (9.0 g, 54 mmol) in portions at 0° C. The mixture was stirred for 0.5 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with sat. aq. NaHCO3 to pH ˜7. The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g 94%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 6.58 (s, 1 H), 6.57 (s, 1 H), 5.98 (s, 2 H), 4.51 (s, 2 H), 3.90 (s, 3 H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([CH2:9][NH2:10])[OH:8]>N1C=CC=CC=1>[OH:8][CH2:7][CH2:9][NH:10][CH:2]([CH2:3][CH3:4])[C:1]([OH:6])=[O:5]
Reactant: NCCO
Reactant: C/C=C/C(=O)O
Solvent: c1ccncc1
Product: CCC(NCCO)C(=O)O

Procedure:
A solution of 86 g of crotonic acid (1 mole) and ethanol-amine (1 mole) in pyridine (200 ml) is refluxed for 2-3 hours and subsequently cooled. The resulting produce is filtered and recrystallized to yield the title compound having m.p. 178°-180° C. (compound 1.1, Table 1). Following analogous procedure, the compounds 1.2-1.7, 1.10, 1.11, and 1.13-1.15 set forth in Table 1 are obtained.