Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1ccc(F)cc1C

Procedure:
A solution of ethyl glyoxalate (50% solution in toluene—40.8 mL) in toluene (180 mL) was heated to reflux for 1.5 hours under a Nitrogen atmosphere, in a flask equipped with a Dean Stark apparatus. Then, a solution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) was slowly added. The mixture was heated to reflux for 3 hours, then it was concentrated in vacuo. The residue was purified by flash chromatography (toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44]12([C:54](Cl)=[O:55])[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]12([C:54]([NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=4)=[O:24])[CH2:18][CH2:19]3)=[O:55])[CH2:51][CH:50]3[CH2:49][CH:48]([CH2:47][CH:46]([CH2:52]3)[CH2:45]1)[CH2:53]2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(CC(C5)C3)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added, in portions, 1-adamantanecarbonyl chloride (0.199 g, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.565 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.267 g colorless crystals. Mp 228° C. Mass spectrum, m+ =491. Anal (C31H43N5O6) theory C, 64.01; H, 7.45; N, 12.04; found C, 63.89; H, 7.53; N, 12.12.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCC>[C:11]1([CH2:10][CH2:9][NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: C=Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(NCCc2ccccc2)cc1
Yield: 84 %

Procedure:
According to GWM, 0.011 mol (=1.10 ml) of p-fluoroaniline and 0.011 mol (=1.25 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:1) as eluent, the product N-(2-phenylethyl)-(p-fluoro)aniline being obtained as brown liquid.
Reaction SMILES: [C:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCO[CH2:34][CH2:33]1.Cl.C(Br)C#C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)[C:33]#[CH:34]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Agent: C#CCBr
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 mL) was added 4 M HCl dioxane solution (0.5 mL) and the mixture stirred for 2 h at 0° C. Solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 mL) and to the mixture was slowly added 80 wt % propargyl bromide solution in toluene (2 μL, 0.020 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 4 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (1:1 n-Hexane/EtOAc) to give a colorless oil (3 mg, 68% yield): 1H NMR (300 MHz, CDCl3) 1.15˜1.87 (m, 20H); 2.14˜2.31 (m, 2H); 2.67˜2.74 (m, 2H); 3.02 (d, J=18.6 Hz, 1H); 3.12˜3.14 (m, 1H); 3.36˜3.39 (m, 2H); 6.81˜6.93 (m, 2H); 7.16 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=[CH2:2].NC1C=CC=CC=1.[CH3:17][O:18][SiH:19]([O:22][CH3:23])[O:20][CH3:21]>[Pt]>[CH:4]12[CH2:9][CH:7]([CH:6]=[CH:5]1)[CH2:8][CH:3]2[CH2:1][CH2:2][Si:19]([O:22][CH3:23])([O:20][CH3:21])[O:18][CH3:17]
Reactant: CO[SiH](OC)OC
Reactant: C=CC1CC2C=CC1C2
Agent: [Pt]
Solvent: Nc1ccccc1
Product: CO[Si](CCC1CC2C=CC1C2)(OC)OC
Temperature: 100 °C

Procedure:
Into a 5 liter round bottom flask, fitted with an addition funnel, Friedrich condenser, thermocouple, stir bar and nitrogen line, were charged 5-vinyl-2-norbornene (1500 grams, 12.48 moles, from Sigma-Aldrich), platinum catalyst (4.5 grams of a 3 wt % solution of platinum(0)-1,3-divinyl-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylenes) and aniline (2.87 grams, 0.031 moles). The reaction mixture was heated gently to 100° C. and then trimethoxysilane (1372.5 grams, 11.23 moles from Momentive Performance Materials, Inc.) was incrementally charged into the flask. The reaction temperature was maintained using (controlling) the rate of addition and heating. The reaction mixture temperature was maintained in a ranged of from 63° C. to 118° C. The mixture was recatalyzed with an additional 1.3 grams of Pt complex and house air was bubbled intermittently into the reaction mixture using a small gage stainless steel needle introduced through a rubber septum. After all the trimethoxysilane had been consumed, the mixture was purified by vacuum distillation. The mono trimethoxysilylated product was isolated at 93° C. and 3 mmHg pressure leaving behind the his trimethoxysilylated constituent.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([NH:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH2:22][CH2:23][C:24]#[N:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.P([O-])([O-])([O-])=O>CN(C=O)C>[C:23]([CH2:24][NH:25][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:10][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:2]([F:1])([F:20])[F:19])#[N:22]
Reactant: CC(C)C[C@H](NC(c1ccccc1)C(F)(F)F)C(=O)O
Reactant: N#CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(c1ccccc1)C(F)(F)F)C(=O)NCC#N
Reaction time: 8 h

Procedure:
A mixture of N-(2,2,2-trifluoro-1-phenylethyl)-L-leucine (149 mg, 0.50 mmol), aminoacetonitrile hydrochloride (102 mg, 1.1 mmol) and PyBOP (260 mg, 0.50 mmol) was dissolved in DMF (5 mL). Triethylamine (0.3 mL, 2.1 mmol) was added and the mixture was stirred overnight, then poured into pH 3 phosphate buffer and extracted with 3:1 ether/ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and evaporated. Purification by ISCO column chromatography (gradient 20% to 50% ethyl acetate/hexanes) provided N1-(cyanomethyl)-N2-(2,2,2-trifluoro-1-phenylethyl)-L-leucinamide as a 1:1 mixture of diastereomers. MS (+APCI): 313.9 [M+1].
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].CCN(CC)CC.[CH:25](=[C:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl.CC(C)=O.CO>[CH:25](=[C:29]1[CH2:34][CH2:33][N:32]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:16])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC=C1CCNCC1
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CO
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(C)cc32)CC1
Yield: 62.7 %

Procedure:
Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.34 g), Et3N (0.5 mL) and 4-butylidenepiperidine (0.17 g, 1.2 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/acetone/MeOH 90:7:3) gave the title compound (0.22 g, 58%). 1H NMR (CD3OD) δ 7.01 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.82 (dm, J=8.0 Hz, 1H), 5.12 (t, J=7.2 Hz, 1H), 4.52 (ABq, J=14.8, 20.8 Hz, 2H), 4.03 (dd, J=5.6, 14.4 Hz, 1H), 3.91 (dd, J=8.0, 14.4 Hz, 1H), 2.48-2.34 (m, 2H), 2.33-2.11 (m, 8H), 2.31 (s, 3H), 1.96 (q, J=7.2 Hz, 2H), 1.34 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CD3OD) δ 165.9, 143.9, 136.0, 132.4, 128.3, 124.3, 122.4, 116.6, 116.2, 67.4, 63.6, 56.3, 55.4, 45.0, 28.92, 28.85, 28.0, 23.0, 20.0, 15.9, 12.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(CCCO)c1cncc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.9 %

Procedure:
To a solution of 1-(5-Bromo-pyridin-3-yl)-4-hydroxy-butan-1-one 1 (5.0 g, 20.5 mmole) in 90 mL of CH2Cl2 at 25° C., was slowly added a solution of Dess-Martin periodinane (9.6 g, 22.5 mmole) in 70 mL of CH2Cl2. After stirring at 25° C. for 20 minutes, the reaction mixture was diluted with 200 mL of ether and cooled by dry-ice-acetone bath. The solid precipitant was filtered away and discarded. The filtrate was concentrated and residue was diluted with 100 mL of ether, cooled with in a dry ice-acetone bath and the precipitant was removed by filtration. The filtrate was concentrated to give 6.2 g of 4-(5-Bromo-pyridin-3-yl)-4-oxo-butyraldehyde 2 as a pale/brown oily liquid which turned to a pale/brown solid after cooled to 0° C., without further purification for next step reaction.
Reaction SMILES: [Cl:1][C:2]1([N+:9]([O-])=O)[CH2:6][N:5]([CH3:7])[N:4]=[C:3]1[CH3:8].[ClH:12].[H][H]>[Pt].CO>[ClH:1].[NH2:9][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH3:7])[C:6]=1[Cl:12]
Reactant: [H][H]
Reactant: CC1=NN(C)CC1(Cl)[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: Cc1nn(C)c(Cl)c1N

Procedure:
4-Chloro-1,3-dimethyl-4-nitropyrazole (described in U.S. Pat. No. 3,282,954) (70.0 g.) was dissolved in 900 ml. methanol and 68 ml. concentrated HCl and hydrogenated over 3.2 g. platinum on carbon. After the hydrogen uptake ceased, the catalyst was filtered, the solvent concentrated in vacuum and the residue crystallized from isopropyl alcohol to get 64.15 g. of product, mp 234°-235° C., decomposed.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:47]=[CH:46][C:13]2[NH:14][C:15]([NH:17][C@H:18]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]4[NH:33][CH2:34][CH2:35][CH2:36][N:37]=4)=[CH:22][CH:21]=3)=[N:16][C:12]=2[CH:11]=1.C1(C)C=CC=CC=1>ClCCl>[CH3:8][O:9][C:10]1[CH:47]=[CH:46][C:13]2[NH:14][C:15]([NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]4[NH:33][CH2:34][CH2:35][CH2:36][N:37]=4)=[CH:22][CH:21]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: COc1ccc2[nH]c(N[C@@H](Cc3ccc(OCCCC(=O)NC4=NCCCN4)cc3)C(=O)OC(C)(C)C)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(N[C@@H](Cc3ccc(OCCCC(=O)NC4=NCCCN4)cc3)C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
2 ml of trifluoroacetic acid is added to 25 mg of ester 4-5a in 5 ml of dichloromethane, followed by agitating for 3 hours at ambient temperature then adding toluene. After evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture, 11 mg of 4-6a is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](OC)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:26])([CH3:25])[C:8]1=[O:27].[CH:28]([NH:31][C@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1)([CH3:30])[CH3:29]>>[CH:28]([N:31]([C:21]([C:14]1[C:15]([C:17]([F:20])([F:18])[F:19])=[CH:16][C:11]2[O:10][C:9]([CH3:26])([CH3:25])[C:8](=[O:27])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:33]1)([CH3:30])[CH3:29]
Reactant: CC(C)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)OC)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21

Procedure:
Using methyl 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3S)-3-(isopropylamino)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1CCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25](=O)[CH3:26])[CH:23]=2)[CH:18]=[N:17]1>C1(C)C=CC=CC=1>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[C:25](=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)/[CH3:26])[CH:23]=2)[CH:18]=[N:17]1
Reactant: CC(=O)c1ccc2cn[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: C/C(=C1\C(=O)Nc2ccccc21)c1ccc2cn[nH]c2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 15.1 %

Procedure:
A solution of oxindole (16 mg, 0.12 mmol), pyrrolidine (10 μL, 0.12 mmol) and 1-(1H-indazol-6-yl)ethanone (20 mg, 0.12 mmol) in toluene was refluxed in a Dean-Stark trap for 2 h. The solution was then stirred at 50° C. for 72 h. Two equivalents of pyrrolidine were added and the solution was heated to reflux for 48 h. The solution was concentrated and the red residue was purified by preparatory HPLC to give the title compound as an orange solid (5 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H, J=8.5 Hz), 7.34 (d, 1H, J=8.5 Hz), 7.03 (t, 1H, J=7.6 Hz), 6.81 (d, 1H, J=7.7 Hz), 6.50 (t, 1H, J=7.6 Hz), 6.05 (d, 1H, J=7.7 Hz), 2.82 (s, 3H); MS ESI [M+H]+, calcd for [C17H13N3O+H]+ 276.1; found m/z 276.0.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1.[N:29]#[C:30]Br>C(Cl)Cl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:30]#[N:29])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Reactant: N#CBr
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C#N)CC2)CCO1
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of 4-amino-5-chloro-2-ethoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}-methyl]benzamide (Example 22) (1.0 g) and TEA (0.41 ml) in methylene chloride (10 ml) was added cyanogen bromide (0.27 g) at room temperature, and then the mixture was stirred for 4 hours, washed with water, then brine and dried over anhydrous magnesium sulfate. Then, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (0.7 g) as a white solid. Melting point 197° C. (degradation, recrystallized from E)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([OH:21])[C:14]([C:18](O)=[O:19])=[N:15][CH:16]=2)[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.C([O:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][NH2:51])C.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([OH:21])[C:14]([C:18]([NH:51][CH2:50][CH2:49][CH2:48][C:47]([OH:46])=[O:52])=[O:19])=[N:15][CH:16]=2)[CH:11]=[C:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCN
Reactant: O=C(O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid (35 mg, 0.094 mmol) and HOBt (13 mg, 0.094 mmol) were added to 2 mL of CH2Cl2. EDC (25 mg, 0.13 mmol) was added, and the mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (16 mg, 0.094 mmol) and Hunig's base (0.033 mL, 0.19 mmol) were then added, and the mixture was stirred for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 13 mg of the title compound. MS: (+) m/z 486.39 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=O.[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[NH2:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([N:5]2[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:7][C:3]([CH:1]=[C:26]([C:24]#[N:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:4]2)=[CH:19][CH:18]=1)(=[O:21])=[O:22]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Yield: 65.8 %

Procedure:
To a solution of the aldehyde from Step 1 (1.2 g, 3.6 mmol) in benzene (18 mL) was added ethyl cyanoacetate (0.38 mL, 3.6 mmol), ammonium acetate (50 mg, 0.7 mmol) and glacial acetic acid (0.17 mL, 2.8 mmol). The solution was heated at reflux for 18 hours, cooled, and partitioned between water and ethyl acetate. The organic solution was washed with a saturated aqueous sodium bicarbonate solution, water and brine. The organic solution was dried and concentrated. The residue was chromatographed on silica (40% hexane in ethyl acetate) to give the desired product (1.0 g, 66%): Anal. calc'd for C21H18N4O4S: C, 59.82; H, 4.30; N, 13.22. Found: C, 59.70; H, 4.29; N, 13.26.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=1.[CH:20]1[N:21]=[CH:22][N:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=12>O1CCCC1>[C:14]([NH:13][C:11](=[O:12])[C:10]1[CH:18]=[CH:19][C:7]([C:25]2([OH:29])[CH2:26][CH2:27][CH2:28][N:23]3[CH:22]=[N:21][CH:20]=[C:24]23)=[CH:8][CH:9]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CCCn2cncc21
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C2(O)CCCn3cncc32)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
11.6 ml of n-butyllithium (1.6M in hexane) are added dropwise to a solution of 4.250 mmol of 4-bromo-N-tert-butylbenzamide in 200 ml of tetrahydrofuran at −78° C. After 90 minutes, a solution of 6.00 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [51907-18-7] in 4 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at −78° C. for 1 hour and at room temperature for 2 hours and then quenched with saturated aqueous ammonium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a yellow solid from the residue by flash chromatography (SiO2 60F). Rf=0.16 (dichlormethane:methanol=95:5), Rt=4.96.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[CH:9]=[N:8][C:7]([N:12](CO)[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:15][C:14]=3[O:26][CH:27]([CH3:29])[CH3:28])=[N:6][C:5]=2[C:4]=1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:39][CH3:40]>C1COCC1.[OH-].[Na+]>[F:38][C:36]1[CH:35]=[CH:34][C:33]([O:39][CH3:40])=[C:32]([C:4]2[C:5]3[N:6]=[C:7]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]5)=[CH:15][C:14]=4[O:26][CH:27]([CH3:29])[CH3:28])[N:8]=[CH:9][C:10]=3[S:11][C:3]=2[CH2:2][OH:1])[CH:37]=1
Reactant: COc1ccc(F)cc1-c1c(CO)sc2cnc(N(CO)c3ccc(N4CCN(C)CC4)cc3OC(C)C)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(CO)sc2cnc(Nc3ccc(N4CCN(C)CC4)cc3OC(C)C)nc12
Yield: 50.4 %

Procedure:
A solution of 517 mg of the {[6-(hydroxymethyl)-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl][4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanol mixture in 24 ml of THF and 10 ml of 1M sodium hydroxide is stirred at ambient temperature for 4 h. The mixture is extracted three times with 10 ml of ethyl acetate. The organic phases are washed with 10 ml of water and the organic phases are concentrated under vacuum. The crude product is purified on 80 g of silica, elution being carried out with 5-8% of methanol in dichloromethane, so as to obtain a yellow foam. After trituration with ether, the resulting solid is filtered off and dried under vacuum, so as to obtain 247 mg of [7-(5-fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]#[N:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.[OH-:16].[Na+].OO>CS(C)=O.C(OCC)(=O)C.O>[CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:16])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CSc1nc(NC2(C)CC2)ncc1C#N
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(NC2(C)CC2)ncc1C(N)=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
To a stirring solution of 2-(1-methylcyclopropylamino)-4-(methylthio)pyrimidine-5-carbonitrile (0.653 g, 2.96 mmol, synthesis described herein) in DMSO (8 mL) was added 6N aqueous sodium hydroxide (2.470 mL, 14.82 mmol) solution and 30% aqueous hydrogen peroxide solution (1.873 mL, 16.52 mmol) at 0° C. Then the mixture was stirred at 50° C. and for 20 minutes and was then diluted with 100 mL ethyl acetate and 30 mL water. The layers were separated and the aqueous layer was back extracted with 50 mL ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated to solids that were dried in a vacuum oven at 45° C. to afford 2-(1-methylcyclopropylamino)-4-(methylthio)pyrimidine-5-carboxamide (305 mg, 1.280 mmol, 43.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31-8.54 (m, 1H), 7.80-8.07 (m, 1H), 6.97-7.77 (m, 1H), 2.39 (br. s., 3H), 1.37 (s, 3H), 0.52-0.79 (m, 4H). MS (ESI) m/z 239.0 [M+1]+.