Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].O>CC(N(C)C)=O>[CH2:12]([C:11]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC=O
Reactant: NC(=O)c1ccccc1N
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Anthranilamide (300 mg, 2.20 mmol) was dissolved under argon in dimethylacetamide (5 ml), valeraldehyde (199 mg, 2.31 mmol) and Na2S2O5 (628 mg, 3.31 mmol) were added, and the mixture was stirred under reflux conditions for 4 h. After cooling to room temperature, water was added to the reaction mixture. By suction-filtering and thoroughly drying the solid formed, 2-butylquinazolin-4(3H)-one (254 mg, 54% of theory) was obtained as a colorless solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.26 (d, 1H), 7.74 (dd, 1H), 7.69 (d, 1H), 7.46 (dd, 1H), 7.30 (br. s, 1H, NH), 2.75 (t, 2H), 1.82 (quint, 2H), 1.49 (sext, 2H), 1.00 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>C(#N)C.CO>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:21])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(F)c1Br
Temperature: 65 °C
Yield: 23 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone (0.44 g, 1.6 mmol) and ammonium acetate (1.8 g, 23 mmol) in acetonitrile (3.0 mL) and methanol (3.0 mL) was heated at 65° C. for an hour. Sodium cyanoborohydride (0.244 g, 3.88 mmol) was added and the mixture was heated at 65° C. overnight. Purification by preparative LCMS (pH=10) gave the desired compound (23% yield). LCMS calculated for C9H8BrClFO (M−NH2)+: m/z=264.9, 266.9. found: 264.9, 266.9. 1H NMR (300 MHz, CDCl3): δ 8.81 (br s, 2H), 7.80 (s, 1H), 4.80 (m, 1H), 3.97 (s, 3H), 1.69 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
2-methoxy-5-nitrophenol (254 mg, 1.5 mmol, 1 eq.) was placed in dimethylformamide (3 mL) with 4-(2-chloro-ethyl)morpholine hydrochloride (837 mg, 4.5 mmol, 3 eq.), Cs2CO3 (3.4 g, 10.7 mmol, 7 eq.), KI (547 mg, 3.3 mmol, 2.2 eq.). The reaction mixture was heated at 80° C. and stirred for 20 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1% NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-(2-(2-methoxy-5-nitrophenoxy)ethyl)morpholine (386 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1(OC)C=CC(CSC2C=CC([F:44])=CC=2)=C(C(OC)=O)C1>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:44])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C1=C(CSc2ccc(F)cc2)C=CC(Br)(OC)C1
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a manner similar to Intermediate 68, starting from methyl 3-bromo-6-(4-fluorophenylthiomethyl)-3-methoxybenzoate (Intermediate 118).
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[C:14](Cl)(Cl)=[O:15]>O1CCOCC1>[Cl:1][C:2]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][CH:6]=[C:5]([Cl:13])[C:3]=1[N:4]=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Solvent: C1COCCO1
Product: O=C=Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-trifluoromethyl-aniline (138 mg, 0.60 mmol) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture is stirred for 2 h at 100° C., cooled to rt and concentrated in vacuo, yielding 2,6-dichloro-3-trifluoromethyl-phenylisocyanate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C)[CH:13]=[O:14]>CO>[CH3:13][O:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCCCBr
Reactant: CN(C)C=O
Solvent: CO
Product: COCCCCCCC(=O)O

Procedure:
The title compound was prepared by the method of Example 1 using 7-bromoheptanoic acid (50 g, 239 mmol) instead of 12-bromoundecanoic acid and dimethylformamide (300 mL) instead or methanol as the solvent. Concentration afforded the title compound (30 g) as a pale yellow liquid and the structure verified by NMR.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:4][C@H:5]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[CH:17]=3)[S:13][CH:14]=2)[CH2:6][CH:7]([CH3:8])[CH3:9])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NS(=O)(=O)c3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 40 mg (0.2 mmol) 4-fluorobenzenesulfonylchloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 85 mg (80%) 4-fluoro-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-benzenesulfonamide as a light yellow solid. MS ISP (m/e): 530.0 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.24 (s, 1H), 8.16 (d, 1H), 7.78-7.65 (m, 3H), 7.23-7.17 (m, 3H), 7.03 (s, 1H), 7.02 (d, 1H), 4.23 (q, 1H), 3.83 (s, 3H), 2.15 (s, 3H), 1.59 (m, 2H), 1.49 (m, 1H), 0.82 (d, 3H), 0.76 (d, 3H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][N:29]=[C:28]3[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=3)[C:44](O)=[O:45])[CH2:37][CH2:36]2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:50][C:51]1[CH:57]=[CH:56][C:54]([NH:55][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:41]([N:38]3[CH2:39][CH2:40][N:35]([C:28]4[C:27]5[C:32](=[CH:33][CH:34]=[C:25]([C:22]6[CH:23]=[CH:24][N:20]([C:1]([C:2]7[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=7)([C:8]7[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=7)[C:14]7[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=7)[N:21]=6)[CH:26]=5)[N:31]=[CH:30][N:29]=4)[CH2:36][CH2:37]3)[CH:42]=2)=[CH:53][CH:52]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cccc(N2CCN(c3ncnc4ccc(-c5ccn(C(c6ccccc6)(c6ccccc6)c6ccccc6)n5)cc34)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1cccc(N2CCN(c3ncnc4ccc(-c5ccn(C(c6ccccc6)(c6ccccc6)c6ccccc6)n5)cc34)CC2)c1
Reaction time: 12 h

Procedure:
200 mg 3-{4-[6-(1-trityl-1H-pyrazolyl)-4-quinazolinyl]piperazin-1-yl} benzoic acid (compound in Example 829), 35 mg 4-fluoroaniline, 46 mg 1-hydroxybenzotriazole and 65 mg 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were dissolved in dichloromethane and stirred for about 12 hours, and the reaction solution was concentrated and purified by silica gel column chromatography to give N1-(4-fluorophenyl)-3-{4-[6-(1-trityl-1H-pyrazolyl)-4-quinazolinyl]piperazin-1-yl}benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:30]([CH3:32])[CH3:31])=[C:6]([CH:29]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH2:10]1.O.NN>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:30]([CH3:32])[CH3:31])=[C:6]([CH:29]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C(C)C)c(OCC2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCN)CC2)c1

Procedure:
17.35 g (0.04 mol) of 2-[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperid-1-yl]propyl]-1H-isoindole-1,3 (2H)-dione are reacted in 340 ml of ethanol with 3.9 ml (0.08 mol) of hydrazine hydrate. The mixture is heated at the reflux temperature for 3 h. The mixture is filtered, the solid being rinsed with a small amount of ethanol, the filtrate is concentrated and taken up in diethyl ether. An insoluble material is again removed by filtration and the filtrate is again concentrated. The insoluble materials are combined in a round-bottomed flask and 25 ml of concentrated hydrochloric acid and 75 ml of water are added. The mixture is brought to reflux for 2 h while stirring. It is allowed to cool, the insoluble material is removed by filtration, rinsing is carried out with water, basification is carried out with concentrated aqueous ammonia and extraction is carried out three times with diethyl ether. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. A compound is obtained which is used as is in the following stage.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2.[I-].[CH3:23][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:1][C@@:2]12[C@:18]3([CH2:23][O:19]3)[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2
Reactant: C[S+](C)C
Reactant: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@@]3(C)[C@@H](CC[C@@]34CO4)C[C@H]12
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of compound 22 (35 mg, 0.12 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to afford compound 23 (23 mg, 63%): mp 138-140° C.; [α]D20 −16.7 (c 0.15, CHCl3); 1H NMR (CDCl3) δ 4.06 (s, br, 1H), 2.90 (d, J=5.1 Hz, 1H), 2.61 (d, J=5.1 Hz, 1H), 0.86 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3) δ 70.5, 66.6, 54.6, 53.6, 47.1, 42.6, 40.2, 39.2, 36.4, 35.8, 35.1, 32.0, 31.8, 29.1, 28.9, 28.8, 25.9, 24.4, 14.4, 11.2; IR νmax 3435, 1007, 758 cm−1. Anal. Calcd for (C20H32O2): C, 78.90; H, 10.59. Found: C, 78.83; H, 10.77.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(-c2ccc(Cl)cc2)c1
Yield: 120.4 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (280 mg, 0.79 mmol) and 4-chlorophenylboronic acid (246 mg, 1.57 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (30 mg) and Na2CO3 (2.5 mL of a 2 M solution), and the mixture was heated at reflux for 6 h. The solvent was removed under vacuum, and the residue was chromatographed (silica gel; EtOAc/hexane, 1:5 to 1:2) to afford the title compound (370 mg, >100% yield): 1H NMR (CDCl3, 300 MHz) δ1.47 (s, 9H), 1.80-2.10 (m, 3H), 3..30-3.49 (m, 2H), 3.90-4.30 (m, 3H), 7.40-7.60 (m, 5H), 8.31 (s, 1H), 8.42 (s, 1H); MS (CI/NH3) m/z 389 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][N:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([NH:32][CH3:33])[N:24]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Ni]>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][N:10]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH:32][CH3:33])[N:24]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1nc(N2CC[C@H](c3cc(F)c(F)cc3F)[C@@H](NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nc(N2CC[C@H](c3cc(F)c(F)cc3F)[C@@H](NC(=O)OC(C)(C)C)C2)ccc1N
Temperature: 40 °C

Procedure:
To a stirring solution of 68 mg (0.14 mmol) of the product of Step B in 8 mL of 10:1 tetrahydrofuran/methanol under nitrogen was added 0.20 mL Raney Nickel (slurry in water). The resulting mixture under hydrogen was heated at 40° C. for 1 h and then cooled to ambient temperature over 24 h. The mixture was then filtered through a pad of Celite and the filter cake washed with dichloromethane and methanol. The combined filtrate and washings were concentrated in vacuo and the resulting purple solid was purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% trifluoroacetic acid) to afford the title compound as a purple crystalline solid. LC/MS 452.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(COc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine (10.4 g) and (4-chlorophenyl)methanol (10 g) in DMF (50 ml) was added potassium carbonate (14.5 g), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water while the product was precipitated out from the reaction medium. The precipitate was collected by filtration and dried under vacuum to give the title compound (4.8 g) as an off-white solid.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].C(O)(=O)C>C(#N)C>[CH2:7]([N:9]([CH2:10][CH3:11])[CH:3]=[CH:4][C:5]#[N:6])[CH3:8]
Reactant: CCNCC
Reactant: N#CC=CO
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(C=CC#N)CC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) is added to a solution of 25.6 g (0.35 mol) of diethylamine, 21.0 g (0.35 mol) of acetic acid and 150 ml of acetonitrile, and the mixture is stirred for 16 h at 25° C. After working up as in Example 50, 19.7 g of 3-diethylaminoacrylonitrile was obtained (63.6%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH:7]=[O:8].C([O-])(=O)C.[K+]>CO.O1CCOCC1.[C].[Pd]>[Cl:22][C:11]1[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[CH:15][C:10]=1[CH2:9][N:5]1[C:6]([CH:7]=[O:8])=[CH:2][N:3]=[C:4]1[CH3:23]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Br)c2C=O)c(Cl)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCOc1ccc(Cn2c(C=O)cnc2C)c(Cl)c1
Reaction time: 3 h
Yield: 96.6 %

Procedure:
4-Bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (4.00 g) was dissolved in a mixed solvent of methanol (20 ml) and 1,4-dioxane (20 ml), and palladium carbon (400 mg) and potassium acetate (1.08 g) were added. The reaction mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with hexane/ethyl acetate=1/2. The objective fraction was concentrated under reduced pressure to give 1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (3.10 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>>[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCN
Reactant: CCOc1cc(Cl)nc2ccccc12
Product: CCOc1cc(NCCCN)nc2ccccc12
Temperature: 60 °C
Reaction time: 48 h
Yield: 76.8 %

Procedure:
To 2-chloro-4-ethoxyquinoline (J. Chem. Soc. Perkin Trans. 1, 1993, 181; 323 mg, 1.56 mmol) was added 1,3-diaminopropane (3.9 ml, 47 mmol). The mixture was stirred under argon at 60° C. for 48 h. Excess diamine was removed in vacuo to leave a cream residue which was purified by flash chromatography on silica gel eluting with 6% (9:1 MeOH/NH3) in DCM to give the title compound as a white solid (294 mg, 77%): δH (CD3OD) 1.49 (3H, t), 1.79 (2H, m), 2.74 (2H, t), 3.51 (2H, t), 4.13 (2H, q), 6.09 (1H, s), 7.12 (1H, t), 7.45 (1H, t), 7.55 (1H, d), 7.90 (1H, d); MS (APCI−) 244 (100%, [M−H]−), 216 (34).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=[C:14]3[C:18]=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.N[C:51]1C=CC(C2C=NN(CCCO)C=2)=CC=1C(NCC)=O>>[CH2:19]([NH:16][C:15]([C:14]1[CH:18]=[C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=2)[CH:11]=[CH:12][C:13]=1[NH:21][C:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:46][CH:47]=2)[N:23]=1)=[O:20])[CH3:51]
Reactant: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2)ncc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-amino-N-ethyl-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]benzamide (Compound 9C, 455 mg, 1.07 mmol) to afford 589 mg of the title compound (81%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=8.8 Hz, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.68 (dd, J=2.2, 8.7 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.23 (dd, J=2.6, 8.7 Hz, 2H), 4.31 (d, J=13.6 Hz, 2H), 3.97-4.08 (m, 4H), 3.57 (t, J=6.2 Hz, 2H), 3.38-3.42 (m, 2H), 3.18-3.25 (m, 2H), 2.10 (quin, J=6.5 Hz, 2H), 1.17-1.26 (m, 9H). MS (ESI): m/z 676.78 [M+H]+. UPLC: tR=1.18 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:11][O:12]C(C)(C)C)=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:11][OH:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]nc1CO
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [3.46 g, Reference Example 42] in dichloromethane (25 ml) was treated with trifluoroacetic acid (25 ml). The mixture was stirred for 1.5 hours and then concentrated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was dried over magnesium sulfate and then evaporated to give 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.49 g) as a brown solid which was used without further purification. LC-MS (METHOD B): RT=2.54 minutes; 171 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:3](=[O:4])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([Cl:20])[CH:10]=[CH:11][C:12]=4[C:13](=[O:19])[C:14]=3[C:15]([OH:17])=[N:30]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Br)cc3)nc(O)c12
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a stirred suspension of dimethyl7-chloro-4-hydroxyquinoiine-2,3-dicarboxylate (1.90 g, 6.40 mM) and 4-bromophenyi hydrazine hydrochloride (10.0 g, 44.7 mM) in ethanol (35mL) was added triethylamine (7.1 mL, 51.1 mM). The resulting brown solutionwas refluxed for 22 hours during which time a tan precipitate formed. This mixture was cooled to room temperature and filtered to give the 4-bromophenyl hydrazine salt of the title compound as a white powder (1.69g). This material was refluxed in glacial acetic acid (20 mL) for 3 hours and cooled to room temperature. The resulting tan suspension was filtered and the solids washed with glacial acetic acid and then ether to give the title compound (1.15 g, 43%) as a tan powder, mp 393°-394° C.; MS(CI): 420 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH:10][C:11]([C:13]([O:15]CC)=[O:14])=[O:12])[S:6][C:7]=1[CH2:8][CH3:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([NH:10][C:11]([C:13]([OH:15])=[O:14])=[O:12])[S:6][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1nc(CC)c(CC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc(NC(=O)C(=O)O)sc1CC
Reaction time: 0.08 h

Procedure:
Ethyl 4,5-diethylthiazol-2-ylcarbamoylcarboxylate (897 mg., 3.5 mmoles), 1 N potassium carbonate (3.5 ml., 3.5 equivalents) and 27 ml. of water were combined and heated on a steam bath for 10 minutes. Clear solution was noted after 5 minutes. The reaction mixture was cooled and made acidic with acetic acid. Crude product (625 mg.) was recovered by filtration. Recrystallization from approximately 33 ml. of absolute ethanol gave purified 4,5-diethylthiazol-2-ylcarbamoylcarboxylic acid [470 mg.; m.p. 206° C. (dec.)].
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH2:18]1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:21]3[CH:22]=[N:17][CH:18]=[N:19][CH:20]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Reactant: BrN1C=CC=NC1
Product: CC(C)(C)c1cc2ncc(C#Cc3cncnc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=278.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 3-bromopyrimidine.