Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: Cn1cc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)O)cc4)sc3n2)cn1
Yield: 37 %

Procedure:
The titled compound (yield=37%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 3.90 (s, 3H) 7.66 (d, J=8.08 Hz, 2H) 7.78 (d, J=8.59 Hz, 1H) 8.04-8.14 (m, 4H) 8.38 (s, 1H) 12.89 (br. s., 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28](N(C)C)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: CN(C)C(=O)c1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: -10 °C

Procedure:
To a solution of 12.9 g (145 mmol) of 2-N,N-dimethylaminoethanol in 100 mL of hexanes, 116 mL (290 mmol) of 2.5 M nBuLi in hexanes was added dropwise with vigorous stirring at −10° C. This mixture was slowly warmed to 0° C., stirred for 30 min, and then 7.54 g (48.6 mmol) of 2-phenylpyridine was added at −10° C. The resulting mixture was stirred for 2 hr at 0° C. and then added dropwise to a solution of 43.2 g (179 mmol) of 16 in 725 mL of THF at −10° C. This mixture was slowly warmed to room temperature, stirred for 12 hr, and then 20 mL of water was added. The organic solvent was evaporated using a rotary evaporator. 17 was isolated from the residue by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-ethyl acetate=5:1, vol.). The obtained product was additionally washed with 30 mL of diethyl ether and then dried in vacuum. Yield 11.0 g (62%) of white solid.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][CH:23]([OH:26])CO)[C:13]3=[O:27])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[NH2:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>>[Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][C:23]([NH:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:26])[C:13]3=[O:27])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: NCC(O)CO
Product: O=C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21)NCC(O)CO
Yield: 47 %

Procedure:
In an similar manner to Example 3, using 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9) as the carboxylic acid and 3-aminopropane-1,2-diol as the amine the title compound (47%) was prepared as a solid.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:32][CH2:33][CH:34]1[O:36][CH2:35]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>O.C(O)(C)C>[ClH:1].[OH:36][CH:34]([CH2:33][O:32][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:35][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CNCCCC[C@H](N)C(=O)O
Yield: 23.6 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 12.0 g of Nε-(2-hydroxy-3-octadecyloxypropyl)-L-lysine hydrochloride (yield 23.6%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])=[CH2:3].C(Cl)Cl.[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C1N2CCN(CC2)C1>>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([NH:19][C:14]([NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2]([CH3:1])=[CH2:3])(=[O:12])=[O:11])=[O:15])[N:21]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: C=C(C)c1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: C=C(C)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(1-methylethenyl)benzenesulfonyl isocyanate in methylene chloride (0.9 g, 4 mmol active ingredient) was added via syringe to a nitrogen purged flask containing a 2-amino-4,6-dimethylpyrimidine and a trace (ca. 10 mg) of DABCO. The mixture was heated to reflux for 3 hours then stirred at room temperature overnight. Evaporation of the mixture left a semisolid residue that was triturated with ether and filtered. In this manner 0.95 g of the title compound was obtained, m.p. 177°-183°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:20](CCC)([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:20]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: CCC[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2ccc(Br)cc12
Yield: 64.9 %

Procedure:
Commercially available 5-bromoindole-3-carboxaldehyde (11.3 g, 50.4 mmol), ammonium hydrogen phosphate (47.0 g, 353 mmol), 1-nitropropane (4.49 g, 50.4 mmol), and glacial acetic acid (100 ml) were heated at a gentle reflux for 18 h. The resulting mixture was concentrated in vacuo and the residue mixed with 5 N sodium hydroxide (500 ml) and ice chips. The precipitate was collected by filtration and rinsed several times with water. The filtrate was concentrated in vacuo to afford 5-bromo-3-cyanoindole (7.23 g, 65%) as a dark solid. 1H-NMR (400 MHz, CDCl3) δ 10.0 (1H, s), 8.68 (1H, br s), 8.51 (1H, s), 7.85 (1H, s), 7.43 (1H, dd, J=8.6, 1.9 Hz), 7.32 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:36]=[CH:35][NH:34][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28](C(=O)C)[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1.[OH-].[K+].CC(O)=O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:36]=[CH:35][NH:34][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cnn(C)c5c4)c4cc[nH]c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cn1ncc2ccc(Nc3nc(Nc4ccc(N5CCNCC5)cc4)nc4[nH]ccc34)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 14.5 %

Procedure:
To a solution of 1-(4-(4-(4-(1-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg, 0.047 mmol) in dioxane (2 mL), aq. 1N KOH (2 mL, 2.00 mmol) was added. The mixture was stirred at 70° C. for 3 h. HOAc (0.3 mL) was added. The mixture was purified by HPLC to give N4-(1-methyl-1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (3 mg), MS 440.3 (M+H) (Compound 22-1); and 1-(4-(4-(4-(1-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (7 mg), MS 482.3 (M+H) (Compound 22-2).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:19]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
In 200 ml of DMF, 41.4 g of N-hydroxyphthalimide and 18 g of potassium carbonate were suspended. Fifty grams of cinnamyl bromide were added, followed by stirring at 120° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled and then poured into about 500 ml of water. Crystals thus precipitated were collected by filtration, dried and then recrystallized from a mixed solvent of acetone and isopropyl ether, thereby obtaining 41.9 g of N-cinnamyloxyphthalimide.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=[C:18]1[C:27]([O:29]CC)=O)[CH2:10]2)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:15]=[CH:14][C:13]2[C:12]3[NH:36][C:27](=[O:29])[C:18]4[N:17]([CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCNC(=O)Cc1ccc2c(c1)CC(n1cc(C(=O)OCC)nc1C(=O)OCC)C2=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Yield: 63.4 %

Procedure:
A mixture of 3.9 g of diethyl 1-[5-(N-ethylaminocarbonylmethyl)-1-oxoindan-2-yl]imidazole-2,4-dicarboxylate, 33.4 g of ammonium acetate and 200 ml of acetic acid is heated at reflux for 3 hours. The reaction mixture is evaporated on a rotary evaporator, 250 ml of distilled water are added to the evaporation residue and the residue is filtered. The solid obtained is washed with distilled water a number of times and dried in an oven. 2.2 g of ethyl 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate are obtained in the form of a light-brown solid melting above 300° C. (1H NMR spectrum in d6-DMSO, T=300K, δ in ppm (300 MHz): 1.05 (3H, t, J=6 Hz, CH3), 1.40 (3H, t, J=6 Hz, CH3), 3.12 (2H, m, NCH2), 3.48 (2H, s, CH2CO), 4.05 (2H, s, CH2), 4.40 (2H, q, J=6 Hz, CH2O), 7.32 (1H, d, J=8 Hz, arom. CH), 7.42 (1H, s, arom. CH), 7.83 (1H, d, J=8 Hz, arom. CH), 8.10 (1H, t, J=5 Hz, NH), 8.60 (1H, s, imidazole H)).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[Cl-].[CH2:33]([O:35][C:36](=[O:48])[CH:37]([OH:47])[CH:38]([NH3+:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:34].[N:49]1[N:50]([C:58]2[N:66]=[CH:65][CH:64]=[CH:63][C:59]=2[C:60](O)=[O:61])[CH:51]=[C:52]2[C:57]=1[CH:56]=[CH:55][CH:54]=[CH:53]2>ClCCl>[N:49]1[N:50]([C:58]2[N:66]=[CH:65][CH:64]=[CH:63][C:59]=2[C:60]([NH:46][CH:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]([OH:47])[C:36]([O:35][CH2:33][CH3:34])=[O:48])=[O:61])[CH:51]=[C:52]2[C:57]=1[CH:56]=[CH:55][CH:54]=[CH:53]2
Reactant: O=C(O)c1cccnc1-n1cc2ccccc2n1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h
Yield: 56.5 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.748 g, 4.60 mmol) and Et3N (1 ml, 7.17 mmol) were successively added to a suspension of 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride (1.303 g, 5.02 mmol) and 2-(2H-indazol-2-yl)nicotinic acid (1 g, 4.18 mmol) in dichloromethane (75 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (750 μl, 5.41 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and poured into 100 ml of water. The precipitate formed was filtered off with suction and dried in vacuo to give 1.05 g of the title compound as an off-white solid.
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].C[O-].[Na+].[CH2:15]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]=[C:4]2[CH:5]3[C:8]([CH3:10])([CH3:9])[C:1]([CH3:11])([CH2:7][CH2:6]3)[C:2]2=[O:3])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: CCCCOc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1

Procedure:
A solution of 100 millimols (15.2 g) of camphor in 250 ml of toluene is heated for 1 hour at the boil with 100 mmols (5.4 g) of sodium methylate. After cooling, 100 mmols (17.8 g) of p-butoxybenzaldehyde are introduced and the mixture is heated at the reflux temperature for 4 hours. The reaction mixture is cooled and 50 ml of water are then added; the toluene phase is separated off, washed with water, dried over sodium sulphate and concentrated to dryness. The solid residue is crystallised from aqueous isopropanol. After drying, 12 g of a white powder, which melts at 62°, are collected.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:31])[CH2:29][N:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:15]=1)[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(-c2nccc(NCc3cccs3)n2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2nccc(N(CC(=O)OC(C)(C)C)Cc3cccs3)n2)cc1

Procedure:
{[2-(4-Isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amino}-acetic acid tert-butyl ester was prepared (149 mg) from [2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amine (135 mg, 0.44 mmol) and bromoacetic acid tert-butyl ester in THF by following the general procedure F. LCMS m/z: 425 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9]CC)=[O:8].C(O)C.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:12]([F:14])([F:13])[F:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(C(F)(F)F)coc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1occ(C(F)(F)F)c1C(=O)O
Yield: 90.6 %

Procedure:
18 g of the product of Stage B were refluxed for 2 and a half hours in 42 ml of water and 126 ml of ethanol in the presence of 3.55 g of sodium hydroxide. The mixture was allowed to return to room temperature and 2N hydrochloric acid was added to neutrality. The mixture was partially concentrated and 2N sodium hydroxide solution was added. The mixture was extracted with isopropyl ether and the solvent was evaporated to obtain 14.25 g of the expected product melting at 140° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)C(=O)C.Cl>>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1
Reactant: CC(=O)N(CCN(C)C)c1ccc(Cl)cn1
Agent: Cl
Product: CN(C)CCNc1ccc(Cl)cn1

Procedure:
A solution of N-(2-dimethylaminoethyl)-N-(5-chloro-2-pyridyl)acetamide (45.5 g, 0.19 mole) in 200 ml of 6 N-hydrochloric acid is stirred at reflux for 16 hours. The excess hydrochloric acid is removed by evaporation under reduced pressure. The oily residue is treated with excess 10 N sodium hydroxide and the product is extracted into ether. The ether extract is dried, filtered and evaporated under reduced pressure. The residual oil is purified by distillation, b.p. 106°-111° at 0.7 mm n25D 1.556. Weight obtained is 32.5 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=O)C.[CH3:41][NH2:42]>CO.C1COCC1>[CH3:41][NH:42][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:3]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg, 0.037 mmol) in 1 mL methanol was added a solution of methylamine in THF (2N, 2 mL). The mixture was stirred at 80° C. for 4 hours. The solvent was removed by vacuum to leave a yellow solid (17 mg, 87%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.60 (br, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.01 (t, J=7.3 Hz, 2H), 2.94 (m, 5H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N6O3: 525.25 (M+H), Found 525.0.
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.S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20]([NH2:23])[CH2:21][CH3:22]>ClCCl>[CH2:20]([NH:23][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:21][CH3:22]
Reactant: CCCN
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)CCc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
3-(4-methoxyphenyl)-propionic acid (8.8 g, 49 mmol) was refluxed in dichloromethane (200 mL) with thionyl-chloride (6.6 mL, 90 mmol) for 1 h. The volatiles were evaporated and the resulting oil was dissolved in dichloromethane (100 mL). This was added to a vigorously stirred mixture of 5% aqueous NaOH (200 mL), dichloromethane (100 mL) and n-propylamine (3.0 mL, 71 mmol). After stirring for 1 h the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and was dried over MgSO4. Evaporation of the solvent gave the amide in quantitative yield (10.7 g, 49 mmol, 100%). IR (neat) cm−3300, 2961; 1734, 1642; MS (EI) m/z 221 (M+) Analyses were in agreement with literature data.
Reaction SMILES: [NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4].[ClH:14].[CH3:15]O>>[ClH:14].[ClH:14].[NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([O:5][CH3:15])=[O:4]
Reactant: CO
Reactant: NC(CF)(Cc1cnc[nH]1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)(CF)Cc1cnc[nH]1

Procedure:
A suspension of 4.4 g (0.024 mole) of 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid in 30 ml of methanol at 0° C. is saturated with dry hydrogen chloride after which the solution is heated under reflux for 12 hours. The solution is then concentrated and allowed to crystallize to afford methyl 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionate, dihydrochloride (4.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(N)c2c1OCCO2
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Reaction time: 8 h
Yield: 98.8 %

Procedure:
37 g (0.165 mol) of ethyl 8-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylate dissolved in 370 ml of dioxane are introduced into a 1 l round-bottomed flask, 23.2 g (0.174 mol) of N-chlorosuccinimide are added, at room temperature and with magnetic stirring, and the mixture is stirred overnight. It is diluted with water, extracted with ethyl acetate and, after the usual processing of the organic phase, 42 g of compound are obtained, which product is recrystallized from a mixture of diethyl ether and diisopropyl ether.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:25])[C:6]1=[O:29]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those described in Example 9. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.15 (1H, br t), 8.54 (1H, s), 7.15 (2H, dd, J=9, 6 Hz), 7.05-7.01 (3H, m), 4.96 (2H, s), 4.11 (2H, s), 3.74 (4H, m), 3.56 (2H, q, J=6 Hz), 3.13 (3H, s), 2.97 (3H, s), 2.59 (2H, t, J=6 Hz), 2.52 (4H, m); HRMS calcd for C26H30FN5O5+H+: 512.2309. Found: 512.2296.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH:17]=2)[N:3]=1.[NH2:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH:17]=2)[N:3]=[C:2]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[CH:7]=1
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(-c3nccs3)no2)n1
Reactant: Cc1cc(N)n[nH]1
Product: COCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3nccs3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-methoxymethyl-2-[2-{3-(thiazol-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 36) and 3-amino-5-methyl-1H-pyrazole.