Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]([S:18]([CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:19])=[CH:6][NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:25][C:22]([F:23])([F:24])[CH2:21][S:18]([CH:5]1[C:3](=[O:2])[C:9]2[C:8](=[C:17]3[C:12](=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[N:16]3)[N:7]=[CH:6]1)(=[O:19])=[O:20]
Reactant: COC(=O)C(=CNc1cccc2cccnc12)S(=O)(=O)CC(F)(F)F
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1c2ccc3cccnc3c2N=CC1S(=O)(=O)CC(F)(F)F
Temperature: 260 °C
Reaction time: 2 h

Procedure:
8-[2-Methoxycarbonyl-2-(2,2,2-trifluoroethylsulfonyl)-ethenylamino]quinoline (4 g) was added to diphenyl ether (100 ml) with stirring at 260° C., and stirring was continued for 2 hours. The mixture was allowed to cool to ambient temperature and hexane (100 ml) was added. The mixture was filtered, and the residue purified by flash chromatography on silica using increasingly polar mixtures of methanol and chloroform as eluant. The product so obtained was recrystallised from acetic acid to give 3-(2,2,2-trifluoroethyl-sulfonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline, mp 272-274° C.
Reaction SMILES: [N+](O[Bi])([O-])=O.[N+](O[Bi])([O-])=O.[N+](O[Bi])([O-])=O.[N+](O[Bi])([O-])=O.O.O.O.O.O.O.O.O.O[Bi:30]=O.[C:32]([OH:40])(=[O:39])[CH:33]([CH2:35][C:36]([OH:38])=[O:37])[OH:34].N.[N+]([O-])([O-])=O>O.OCC(CO)O>[C:32]([O-:40])(=[O:39])[CH:33]([CH2:35][C:36]([O-:38])=[O:37])[OH:34].[Bi+3:30].[C:32]([O-:40])(=[O:39])[CH:33]([CH2:35][C:36]([O-:38])=[O:37])[OH:34].[C:32]([O-:40])(=[O:39])[CH:33]([CH2:35][C:36]([O-:38])=[O:37])[OH:34].[Bi+3:30]
Reactant: O=[Bi]O
Reactant: O=C(O)CC(O)C(=O)O
Agent: N
Agent: O=[N+]([O-])O[Bi]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: OCC(O)CO
Product: O=C([O-])CC(O)C(=O)[O-]
Product: [Bi+3]
Temperature: 70 °C

Procedure:
The bismuth sub nitrate, glycerin, malic acid, ammonia, and 10% of the water were placed in a kettle and heated at 70° C. until clear. During heating, the malic acid displaced the nitrate to form bismuth malate, which complexed with the ammonia;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.O.Cl>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc([N+](=O)[O-])ccc1CO
Temperature: 65 °C

Procedure:
A stirred solution of 2-amino-4-nitrobenzoic acid (Aldrich; 18.2 g, 100 mmol) in dry THF (500 mL) at 20° C., is treated with a solution of borane-THF complex (BH3-THF; Fluka; 100 mL of 1.0 M), dropwise over 45 min to regulate the gas evolution. The mixture is then heated at 65° C. for 2 h. The stirred mixture is then cooled to 0° C., treated with water (20 mL) and warmed to RT. Upon the cessation of gas evolution, hydrochloric acid (20 mL of 12 M) is added and the mixture is then heated at 65° C. for 30 min. The cooled mixture is then concentrated to a volume of circa 150 mL by rotary evaporation under reduced pressure to give a suspension. The suspension is filtered and the precipitate is redissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium hydrogen carbonate (2×150 mL). The solution is dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give the title compound as a yellow crystalline solid, m.p. 126-128° C.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][O:30][CH3:31]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][O:30][CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: COCC(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: COCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-methoxy-acetamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.61 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1)[CH:32]=[CH2:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Reactant: C=CCN
Product: C=CCNc1nccc(Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)n1

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.2 g) and allylamine (0.4 ml) was stirred and heated to reflux for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.135 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 3.5 (m, 4H), 3.7 (m, 4H), 3.82 (m, 2H), 4.95 (m, 1H), 5.05 (m, 1H), 5.85 (m, 2H), 6.57 (br m, 1H), 7.07 (m, 1H), 7.17 (m, 2H), 7.43 (m, 1H), 7.78 (m, 1H), 7.87 (br m, 1H), 8.24 (m, 1H), 8.37 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:15][CH2:14][N:13]([C@H:16]([CH3:20])[CH2:17][C:18]#[N:19])[CH2:12][CH2:11]1.[CH3:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([CH3:31])[N:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:28]([C:27]3[C:22]([CH3:21])=[N:23][CH:24]=[N:25][C:26]=3[CH3:31])=[O:29])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)cc1
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(Cl)cc2)CC1
Yield: 86.3 %

Procedure:
Using general procedure A with 4-chloroaniline (230 mg, 1.80 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (263 mg, 1.58 mmol), then general procedure J and then using general procedure E with the resulting amine and 4,6-dimethyl-pyrimidine-5-carboxylic acid (100 mg, 0.66 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-butyl}-amide (237 mg, 35% over 3 steps).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C:17]1[C:22]([CH:23]2[N:28]3[C:29](=[O:42])[NH:30][C:31]4=[CH:32][CH:33]=[C:34]([C:35]5[C:36]([CH3:41])=[N:37][O:38][C:39]=5[CH3:40])[C:26](=[C:27]34)[O:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>C(Cl)Cl>[CH3:41][C:36]1[C:35]([C:34]2[C:26]3[O:25][CH2:24][CH:23]([C:22]4[C:17]([CH2:16][NH:15][C:3](=[O:4])[CH3:2])=[N:18][CH:19]=[CH:20][CH:21]=4)[N:28]4[C:29](=[O:42])[NH:30][C:31]([C:27]=34)=[CH:32][CH:33]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1CN
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1ncccc1C1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Yield: 74 %

Procedure:
A solution of 4-[2-(aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one bis(trifluoroacetate) (35.0 mg, 0.058 mmol) in methylene chloride (2.0 mL) was treated with N,N-diisopropylethylamine (50.3 μL, 0.289 mmol) and stirred. Once the starting material was completely dissolved, the reaction mixture was treated with acetyl chloride (49.3 μL, 0.069 mmol) (added as a 10% solution in dichloromethane) and stirred at room temperature for 1 h. The reaction mixture was quenched with methanol and the solvent was concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (18 mg, 74%) as a racemic mixture. 1H NMR (500 MHz, DMSO-d6) δ 10.98 (br s, 1H), 8.50-8.47 (m, 1H), 8.44 (dd, J=5.2, 5.2 Hz, 1H), 7.26 (dd, J=7.9, 4.7 Hz, 1H), 7.23-7.16 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.68 (dd, J=3.1, 3.1 Hz, 1H), 4.71 (dd, J=15.1, 6.1 Hz, 1H), 4.55-4.47 (m, 2H), 4.44 (dd, J=11.6, 3.2 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.88 (s, 3H); LCMS calculated for C22H22N5O4 (M+H)+: m/z=420.2. found: 420.1.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[C:12]1[NH:16][N:15]([CH3:17])[C:14](=[O:18])[CH:13]=1.Cl[CH:20]([F:22])[F:21]>O.O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[C:12]1[CH:13]=[C:14]([O:18][CH:20]([F:22])[F:21])[N:15]([CH3:17])[N:16]=1
Reactant: Cc1cc(-c2cc(=O)n(C)[nH]2)c(Cl)cc1Cl
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl

Procedure:
28.8 g (720 mmol) of sodium hydroxide dissolved in 240 ml of water were added to a solution of 37 g (144 mmol) of 5-(2,4-dichloro-5-methylphenyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one in 390 ml of dioxane. Chlorodifluoromethane was subsequently passed in at 60-65° C. in the course of 4 hours, whereupon the reaction solution was stirred into 1 l of water. It was then extracted using methyl tert-butyl ether. The organic phase was dried over magnesium sulfate, filtered and then concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: diethyl ether). Yield: 35.1 g.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:37]3[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=3)[CH:24]=2)[C:19]1=[O:43].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:37]5[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=5)[CH:24]=4)[C:19](=[O:43])[N:18]([CH3:17])[CH:27]=3)=[N:3][C:4]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[N:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4nc(NS(C)(=O)=O)ncc4OCC4CC4)c3c2)cn1

Procedure:
The title compound of Example 152, step 4 was reacted with the title compound of Example 46 step 2 in a manner similar to Example 152, step 5 and the resulting product was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 11.15 (s, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.77 (d, J=9.6 Hz, 1H), 7.70 (s, 1H), 3.95 (d, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.57 (s, 3H), 3.32 (s, 3H), 1.00-0.99 (m, 1H), 0.37-0.32 (m, 2H), 0.14-0.12 (m, 2H). LCMS: 481.0 (M+1)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.O1CCOCC1.[CH3:18][NH2:19].CO>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:19][CH3:18]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask was added 4-bromo-2-fluoro-1-nitrobenzene (11.8 g, 53.7 mmol), anhydrous 1,4 Dioxane (100 mL), and a 2.0 M solution of methyl amine in methanol (56.4 mL, 113 mmol). The reaction mixture was then heated to 90° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 3.5 hours. The crude reaction mixture was then allowed to cool to room temperature, and concentrated to give 5-bromo-N-methyl-2-nitroaniline (1-1). MS (M)+: observed=230.9, calculated=231.05.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11]COC.O.Cl.[O-]S([O-])(=O)=O.[Ca+2]>CO.C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: COCOc1ccc(/C=C/c2ccc(S(=O)(=O)N3CCOCC3)cc2)cc1OCOC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(/C=C/c2ccc(O)c(O)c2)cc1)N1CCOCC1
Reaction time: 45 h
Yield: 91 %

Procedure:
N{4-[2-(3,4-Di(methoxymethoxy)phenyl)-trans-vinyl]benzenesulfonyl} morpholine (0.6 g, 1.3347 mmol) was dissolved in a mixed solvent of MeOH (100 mL) and CH2Cl2 (60 mL). The homogeneous solution was bubbled with argon gas. Water (0.2 g, 11.11 mmol) and concentrated hydrochloric acid (0.9 mL, 10.8 mmol) were added and stirred for 45 hours. The solvents were removed by evaporation and the solid residue was washed with water for several times. The solid was dried under high vacuum in the presence of Drierite providing 0.4388 g of N-{4-[2-(3,4-dihydroxyphenyl)-trans-vinyl]benzenesulfonyl}-morpholine as a yellowish solid (1.214 mmol, yield 91.0%). 1H NMR (Acetone-D6 and DMSO-d6, 300.16 MHz) δ (ppm) 9.05 & 9.03 (2s, 0.64H), 8.81 & 8.79 (2s, 0.65H), 7.81 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 7.32 (d, J=16.3 Hz, 1H), 7.13-7.04 (m, 2H), 6.96 (dd, J=8.2 & 1.9 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 3.68-3.65 (m, 4H) and 2.94-2.91 (m, 4H). MS (ESI) m/z: 362 (M+1)+, 384 (M+23)+ and 745 (2M+23)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.[NH2:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:15][C@@H:16]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 40.1 %

Procedure:
Then, 3-(4-methoxyphenyl)propionic acid (330 mg, 1.83 mmol) and ethyl (S)-2-amino-3-(4-nitrophenyl)propionate hydrochloride (500 mg, 1.82 mmol) were dissolved in N,N-dimethylformamide (30 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (384 mg, 2.00 mmol), 1-hydroxy-1H-benzotriazole (270 mg, 2.00 mmol) and N-methylmorpholine (0.25 ml, 2.27 mmol) were added, and the mixture was stirred at room temperature for 21hours. Water (500 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away, from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give 292 mg of ethyl (S)-2-[3-(4-methoxyphenyl)propionylamino]-3-(4-nitrophenyl)propionate as a colorless solid (40%). This solid (280 mg, 0.699 mmol) was dissolved in ethanol (30 ml) and 10% palladium-carbon (100 mg) was added. The mixture was refluxed under heating for 14 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature and filtrated. Low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-3/7) to give 171 mg of ethyl (S)-3-(4-aminophenyl)-2-[3-(4-methoxyphenyl) propionyl-amino]propionate as a colorless solid (66%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:24](CC4C=CC=CC=4)[N:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[F:32])([CH3:12])[N:3]=1.[ClH:33]>CO.O1CCOCC1.[Pd]>[ClH:33].[NH:24]1[C:20]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:32])=[C:13]([C@@:4]3([CH3:12])[N:3]=[C:2]([NH2:1])[N:7]([CH3:8])[C:6](=[O:9])[C:5]3([CH3:10])[CH3:11])[CH:18]=2)=[CH:21][CH:22]=[N:23]1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccnn3Cc3ccccc3)ccc2F)N=C1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccn[nH]3)ccc2F)N=C1N
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-6-(5-(1-benzyl-1H-pyrazol-5-ylamino)-2-fluorophenyl)-3,5,5,6-tetramethyl-5,6-dihydropyrimidin-4(3H)-one (example 107, 0.02 mmole) in methanol (1 ml) was added a solution of aqueous 4M HCl in 1,4-dioxane (0.25 ml) and Pd/C (10%, 3 mg) under argon. The reaction mixture was hydrogenated at 1 atm H2 for 2 h, filtered over Decalite and the residue was washed with methanol. The filtrate was concentrated in vacuo and the residue purified by flash chromatography on NH2-silica using a gradient of dichloromethane/methanol to yield the title compound as a colorless waxy solid. MS (ESI): m/z=345.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1CCCCC1.C1CCN2C(=NCCC2)CC1.[CH:27]([OH:31])(CC)[CH3:28]>>[CH:3]1[CH:2]=[CH:9][C:8]2[O:31][CH2:27][CH2:28][C:6](=[O:7])[C:5]=2[CH:4]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: CCC(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCNCC1
Product: O=C1CCOc2ccccc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of protected hydroxyarylketone (1.0 equiv), 4-iodobenzaldehyde (1.0 equiv), piperidine (0.35 equiv), and DBU (0.35 equiv) in s-butanol (1.0 M) was heated at reflux. Using a Dean-Stark trap, half of the solvent was removed over 30-40 min, and the reaction was kept at reflux without further concentration for additional 4-8 h. The reaction mixture was cooled to 90° C., i-propanol (0.7-1.0 fold of s-butanol v/v) was added, and the reaction was allowed to cool to room temperature. Any large pieces of material were broken down with a spatula, and the suspension was stirred overnight (Note #1 & 2). The precipitate was collected by filtration to give the corresponding chromanone.
Reaction SMILES: [P:1](Cl)(Cl)[O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[C:17]([CH3:20])([CH3:19])[CH3:18].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].C(N(CC)CC)C>C(Cl)Cl>[C:17]([C:4]1[CH:5]=[C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:2][P:1]1[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(OP(Cl)Cl)c(C(C)(C)C)c1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP2Nc3ccccc3O2)c(C(C)(C)C)c1
Yield: 26.5 %

Procedure:
Using the general procedure of Example 1, 12.0 g (33 mmol) of 2,4,6-tri-tert-butylphenyl phosphorodichloridite, 3.6 g (33 mmol) of 2-aminophenol, 9.3 ml (66 mmol) of triethylamine and 75 ml of methylene chloride are reacted to give 3.5 g of the title compound as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:9]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:10])[CH3:8]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O

Procedure:
Ethyl bromoacetate (0.62 mL) was added to a mixture of 5-bromo-2-hydroxyacetophenone (1.0 g) and potassium carbonate (0.96 g) in N,N-dimethylformamide (10 mL) at room temperature with stirring, and the mixture was stirred at that temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl (2-acetyl-4-bromophenoxy)acetate as a crude product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[CH3:16])=[CH2:5])C.O>C1COCC1.Cl>[F:15][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:16])=[C:6]([C:4](=[O:3])[CH3:5])[CH:14]=1
Reactant: C=C(OCC)c1cc(F)cc2c1cnn2C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(F)cc2c1cnn2C
Yield: 55.6 %

Procedure:
A solution of 4-(1-ethoxyvinyl)-6-fluoro-1-methyl-1H-indazole (1.24 g, 5.62 mmol) in THF (10 mL) and aqueous HCl (2.0 N, 10 mL) was stirred at RT for 2 h then poured into water (200 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with an aqueous NH4OH (30 mL) and brine (50 mL), dried (MgSO4), filtered, and evaporated in vacuo to afford 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone as a white solid (600 mg, 55%). MS (ESI): m/z=193.2 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.Cl.[N:19]([O-])=O.[Na+].[C:23]([OH:32])(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:26]>O.[OH-].[Na+].CCOC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]=[N:19][C:29]2[CH:28]=[CH:27][C:25]([OH:26])=[C:24]([CH:30]=2)[C:23]([OH:32])=[O:31])=[CH:13][CH:12]=1
Reactant: Nc1ccc(OCCCCCCCCBr)cc1
Reactant: O=C(O)c1ccccc1O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(N=Nc2ccc(OCCCCCCCCBr)cc2)ccc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
4-(8-Bromooctyloxy)aniline (2.30 g, 7.7 mmol) was suspended in a mixture of concentrated hydrochloric acid (mL) and water (75 mL). The resulting solution was cooled to 0° C. in an ice bath. Sodium nitrite (0.83 g, 12.1 mmol) in water (10 mL) was added dropwise to the reaction mixture with rapid stirring over about 20 min. The reaction mixture was stirred for an additional 20 min while salicylic acid (3.68 g, 26.6 mmol) was dissolved in an aqueous NaOH solution (8.0 g NaOH in 100 mL H2O). This basic salicylic acid solution was vigorously stirred at 0° C. and the solution of the diazonium salt added dropwise. The pH was maintained at 12-14 by adding 8M NaOH solution. After the addition was complete, the solution was allowed to warm to room temperature and was stirred for an additional 30 min. The mixture was diluted with EtOAc (100 mL), washed with water (3×20 mL), 5% NaHCO3 (2×20 mL), brine, dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and methanol (98:2) as elutant. The product (1.40 g, 3.1 mmol, 40%) was obtained as a red-brown solid, mp 180-182° C. 1H NMR (500 MHz, CDCl3) δ 1.25-1.44 (m, 8H), 1.72-1.85 (m, 4H), 3.38 (t, J=Hz, 2H), 3.93 (t, J=6.5 Hz, 2H), 6.86-6.91 (m, 3H), 7.69 (d, J=Hz, 2H), 7.84 (dd, J=10 Hz, Hz, 1H), 8.42 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.8, 25.9, 28.0, 28.5, 29.0, 29.1, 29.2, 31.7, 32.7, 33.9, 35.2, 68.1, 113.3, 118.4, 123.1, 124.0, 126.1, 127.5, 144.9, 146.5, 161.0; HRMS (ESI) calculated for C21H26BrN2O4 (M+H)+449.1070, observed 449.1063.