Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH:5]([OH:8])[CH2:6][N:7]=1.S(Cl)(Cl)=O.[C:13](O)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[NH:7][CH2:6][CH:5]([O:8][C:13](=[O:15])[CH3:14])[CH2:4][N:3]=1
Reactant: CC1=NCC(O)CN1
Reactant: CC(=O)O
Solvent: O=S(Cl)Cl
Product: CC(=O)OC1CN=C(C)NC1

Procedure:
2-Methyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine (JOC 1966, 31, 3838; 1.5 g, 13.3 mmol) was dissolved in glacial acetic acid (100 ml) with stirring, and thionyl chloride (1 ml, 13.1 mmol ) was added dropwise. The resulting solution was refluxed 19 hours, then evaporated to dryness in vacuo. The residue was taken up in water (5 ml), the pH adjusted to 9 (sat. Na2CO3), extracted with chloroform and the organics discarded. The aqueous layer was then adjusted to pH 12 (sat. NaOH) and extracted with chloroform. The chloroform was dried (MgSO4) and evaporated in vacuo to 575 mg (28%) white crystals, mp 141°-146° C. 400 MHz nmr confirmed the product calculated: C 53.82, H 7.75, N 17.94; found: C 53.9, H 7.73, N 17.77.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][O:23]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:20][C:7]1=2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:43][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][OH:23])=[CH:20][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCC=C1c2ccccc2COc2ccc(CCO)cc21
Yield: 76.1 %

Procedure:
In this example, 0.92 g of 11-(3-dimethylaminopropylidene)-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in a mixed solvent of 20 ml of water and 20 ml of dioxane. To the solution is added 60 mg of p-toluene sulfonic acid and the mixture is heated at reflux for two hours. The solvent is distilled away under reduced pressure and the residue is extracted with 200 ml of ethylacetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium hydrochloride solution in oder and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: ethylacetate triethylamine=10:1 ) to obtain 0.4 g of the desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([OH:28])=O)[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), ethyl 3-aminopropanoate hydrochloride (6.71 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=477.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24].[CH2:26]([N:28]1[CH:33]=[C:32]([C:34](O)=[O:35])[C:31](=[O:37])[N:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C:29]1=[O:45])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:34]([C:32]2[C:31](=[O:37])[N:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:29](=[O:45])[N:28]([CH2:26][CH3:27])[CH:33]=2)=[O:35])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(C)C)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C(C)C)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=173-175° C.; LCMS m/z=599 (M+1); 1H NMR (DMSO-d6) δ: 10.93 (s, 1H), 8.80 (s, 1H), 8.45 (d, 1H, J=6 Hz), 7.76 (dd, 1H, J=2, 8 Hz), 7.68 (d, 1H, J=2 Hz), 7.55 (s, 1H), 7.46-7.33 (m, 5H), 7.16 (d, 1H, J=8 Hz), 6.36 (d, 1H, J=5 Hz), 4.01 (q, 2H, J=8 Hz), 3.94 (d, 6H), 2.99 (m, 1H), 1.3 (t, 3H, J=7 Hz), 1.14 (d, 6H, J=7 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[N:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)(=O)C>C(O)CCC>[CH2:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]
Reactant: CCC1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 160 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of 1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (42 mg) obtained in Step A, 4-(morpholin-4-yl)aniline (39 mg) and acetic acid (11 μL) in 1-butanol (2 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:7][N:6]([C:8]2[C:21]([F:22])=[CH:20][C:11]([C:12]([NH:14][C@@H:15]([CH:17]3[CH2:19][CH2:18]3)[CH3:16])=[O:13])=[C:10]([F:23])[CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:7][N:6]([C:8]2[C:21]([F:22])=[CH:20][C:11]([C:12]([NH:14][C@@H:15]([CH:17]3[CH2:18][CH2:19]3)[CH3:16])=[O:13])=[C:10]([F:23])[CH:9]=2)[CH2:5]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide (0.48 g) was dissolved in a solution of trifluoroacetic acid (3 mL, 40 mmol) in methylene chloride (3 mL). The solution was stirred at room temperature for 1.5 hours. It was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL). To the solution was added ethylenediamine (3 mL). The mixture was stirred at room temperature for 2 hours. After concentration the crude material was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-10%) to afford the desired product (245 mg, 24%). LCMS (M+H)+: m/z=503.2. 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 9.08 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 7.84 (dd, J=8.0, 4.0 Hz, 1H), 7.78 (m, 1H), 7.36 (dd, J=13.0, 7.0 Hz, 1H), 7.23 (m, 1H), 6.64 (dd, J=13.0, 7.0 Hz, 1H), 4.70 (d, J=8.0 Hz, 2H), 4.45 (d, J=8.0 Hz, 2H), 3.78 (s, 2H), 3.43 (m, 1H), 1.09 (d, J=6.5 Hz, 6H), 0.97 (m, 1H), 0.43 (m, 1H), 0.37 (m, 1H), 0.28 (m, 1H), 0.19 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: Cc1ccccc1B(O)O
Reactant: N#Cc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C#N)cc1
Yield: 93.1 %

Procedure:
4-Chlorobenzonitrile (55 mg, 0.40 mmol) reacted with 2-methylphenylboronic acid (82 mg, 0.60 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (70 mg, 1.21 mmol) in THF at 45° C. to give the title compound (72 mg, 94%) as a white solid: 1H-NMR (300 MHz, CDCl3): δ 7.73 (d, 2H, J=8.1 Hz), 7.46 (d, 2H, J=8.4 Hz), 7.27-7.34 (m, 3H), 7.21, (d, 1H, J=6.9 Hz), 2.80 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.76, 139.97, 135.00, 131.94, 130.64, 129.97, 129.39, 128.26, 126.07, 118.93, 110.70, 20.28. GC/MS (EI): m/z 193 (M+), 165.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccc(Br)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (480 mg, 2.09 mmol), (4-bromo-phenyl)-acetic acid (449 mg, 2.09 mmol), ethyldimethylpropylcarbodiimide hydrochloride (470 mg, 2.23 mmol), N-hydroxybenzotriazole (330 mg, 2.44 mmol), N-methyl morpholine (500 mg, 5.00 mmol) in 20 mL of DMF was shaken for 6 hours, concentrated under reduced pressure and the residue purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.98 (m, 2 H), 3.01 (m, 2 H), 3.50 (m, 2 H), 3.79 (m, 4 H), 4.66 (t, J=6.24 Hz, 2 H), 7.12 (m, 1 H), 7.32 (m, 2 H), 7.54 (m, 2 H), 7.72 (m, 1 H), 8.08 (s, 1 H), 8.25 (s, 1 H), 10.44 (s, 1 H); MS (DCI/NH3) m/z 429 [M+H]+.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].[N:9]1[C:16]([Cl:17])=[N:15][C:13](Cl)=[N:12][C:10]=1[Cl:11].C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:11][C:10]1[N:9]=[C:16]([Cl:17])[N:15]=[C:13]([N:6]2[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]2)[N:12]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=CN1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reaction time: 4 h
Yield: 35.2 %

Procedure:
1-Formylpiperazine (5.0 g) in dry acetone (28 ml) was added dropwise to a stirred suspension of cyanuric chloride (6.2 g) and sodium bicarbonate (2.58 g) in dry acetone (153 ml) at -35°. The reaction mixture was stirred at -30° for 13/4 hours. Insoluble material was removed by filtration and washed with acetone. The combined filtrate and washings were evaporated in vacuo and the residue taken up in methylene chloride, filtered and the filtrate evaporated in vacuo. The resulting solid was re-crystallized twice from ethyl acetate to give in two fractions 4,6-dichloro-2-(4-formylpiperazino)1,3,5-triazine (3.1 g) m.p. 163°-165°.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:34])[C@H:11]([N:15]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[OH:8][NH:9][C:10](=[O:34])[C@H:11]([N:15]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOCc2ccccc2)C(C)C)cc1
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)C(C)C)cc1

Procedure:
N-Benzyloxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide (see example 29a) is reacted with hydrogen in the presence of 10% palladium on charcoal catalyst at room temperature and atmospheric pressure to yield N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]3-methylbutanamide. After conversion to the hydrochloride salt, a white solid is obtained, m.p. 169°-170° C. (dec).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([OH:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:18][C:12]1[CH:11]=[C:10]([Br:9])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Benzyl bromide (1.35 ml) was added to a mixture of 4-bromo-2-hydroxybenzaldehyde (2.07 g) and potassium carbonate (1.38 g) in DMF (20 ml) and the mixture was stirred at ambient temperature for 10 hours. The reaction mixture was poured into water (50 ml) to give 2-benzyloxy-4-bromobenzaldehyde as a solid which was filtered and dried, yield 2.88 g. The material was used in subsequent reactions without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:7].[N:28]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19]([NH:36][CH2:35][CH2:34][CH2:33][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[N:18]=[CH:17][N:16]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(Cl)ncn1
Reactant: NCCCN1CCCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(NCCCN2CCCC2)ncn1

Procedure:
A mixture of 4-[5-(3-dimethylaminobenzamido)-2-methylanilino]-6-chloropyrimidine (0.114 g), 3-pyrrolidin-1-ylpropylamine (0.95 ml), N,N-di-isopropylethylamine (0.063 ml) and n-butanol (2 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 10:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.124 g); NMR Spectrum: (DMSOd6) 1.59 (m, 6H), 2.15 (s, 3H), 2.34 (m, 6H), 2.93 (s, 6H), 3.14 (m, 2H), 6.72 (m, 1H), 6.89 (m, 1H), 7.2 (m, 4H), 7.3 (m, 1H), 7.5 (m, 1H), 7.72 (m, 1H), 7.96 (m, 1H), 8.16 (s, 1H), 10.02 (s, 1H); Mass Spectrum: M+H+ 474.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:46].O1CCOCC1>>[ClH:46].[C:11]1([C@H:9]([NH:8][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=3)=[O:29])[CH2:24][CH:23]2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)Nc2ccc(C(=O)O)cc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(C(=O)Nc2ccc(C(=O)O)cc2)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 289 mg of the crude product of 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)benzoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then heated under reflux for dissolution in isopropanol. Diisopropylether was added dropwise thereto, and the precipitate was isolated by filtration, and dried under reduced pressure to obtain 159 mg of 4-({[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH2:23]2)=[CH:18][C:17]=1[OH:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[C:17]([OH:26])[CH:18]=4)[CH2:23]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1O)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1cc2c(cc1O)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:10])[S-:9].[CH2:11]([NH+](CC)CC)C.CN(C)C=O.C(N(CC)CC)C.C(Br)Br>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]1[S:9][CH2:11][S:10]1
Reactant: CC[NH+](CC)CC
Reactant: S=C([S-])Nc1ccccn1
Solvent: CN(C)C=O
Solvent: BrCBr
Solvent: O
Product: c1ccc(N=C2SCS2)nc1
Reaction time: 1.5 h

Procedure:
Triethylammonium 2-pyridyldithiocarbamate (27.1 g.) was dissolved in 100 ml. of dimethylformamide and added dropwise to a stirred mixture of 14 ml. of triethylamine and 36.3 ml. of methylene bromide in 65 ml. of dimethylformamide. After addition was complete, the mixture was stirred another 1.5 hr. and then poured into water. The resulting mixture was extracted with ether and, after being washed with water, the ether mixture was extracted with several portions of 3N sulfuric acid. The aqueous extract was cooled in an ice bath and then made alkaline with 8N sodium hydroxide. The product was collected by filtration and washed with water. The crude dry product (12.0 g.) was recrystallized from ethanol to give 10.1 g. of colorless solid, m.p. 98.7°-99.7°C.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)[C@H:16]([CH2:26][O:27]CC4C=CC=CC=4)[O:15][C:14]3=[O:35])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)[C@H:16]([CH2:26][OH:27])[O:15][C:14]3=[O:35])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1O[C@@H](COCc2ccccc2)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1O[C@@H](CO)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
The title compound was obtained as a colorless oil from 1-((E)-3-(benzyloxy)prop-1-enyl)-3,5-difluorobenzene by the same method that is described for Example 39. (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one (Example 96) was placed into a 25 mL round bottom flask and dissolved in 7 mL ethanol:ethyl acetate (1:1) and treated with palladium on carbon (10% by weight, 73 mg). The vessel was sealed with a rubber septum and charged with hydrogen. The reaction was stirred for 2 h, then filtered on celite, evaporated to dryness and purified on silica gel (20-30% ethyl acetate/hexanes) to give the title compound as a colorless oil that solidified on standing. 1H NMR (acetone-d6) δ (ppm) 7.53 (d, J=9.1 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.21-7.16 (m, 2H), d, J=6.15 Hz, 2H), 7.02-6.93 (m, 5H), 5.58 (d, J=5.4 Hz, 1H), 4.55 (t, J=5.8 Hz, 1H), 4.45 (ddd, J=5.6, 3.7, 3.6), 3.97 (ddd, J=12.3, 5.6, 3.8 Hz, 1H), 3.90 (ddd, J=12.3, 5.6, 3.8 Hz, 1H); HPLC-MS calculated C22H16ClF2NO4 (M+H+): 432.1, found: 432.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](Cl)=[N:9][C:10]=2Cl)[CH:5]=[C:4](Cl)[N:3]=1.C([O-])(=O)C.[K+]>CO.[Pd]>[CH2:10]1[C:11]2[C:6](=[CH:5][CH:4]=[N:3][CH:2]=2)[CH2:7][CH2:8][NH:9]1
Reactant: Clc1cc2cc(Cl)nc(Cl)c2c(Cl)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: c1cc2c(cn1)CNCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 125.6 %

Procedure:
A mixture of 1,3,6,8-tetrachloro-2,7-naphthyridine (1.00 g, 2.67 mmol, 1 eq), Pd/C (200 mg, 0.2 eq) and potassium acetate (6.00 g, 61 mmol, 16 eq) in 300 mL of MeOH was stirred for 24 h at room temperature under H2, and then filtered through a Celite pad. The filtrate was concentrated in vacuo and treated with 100 mL of saturated Na2CO3 aqueous solution. The mixture was extracted with CH2Cl2 (50 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound as pale yellow oil (450 mg, 90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 135.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.95 (2H, m), 3.38 (2H, m), 3.83 (2H, s), 7.08 (1H, m), 8.14 (1H, m), 8.28 (1H, m) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20](Br)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([NH2:31])(=[O:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([NH:31][C:28](=[O:30])[CH3:29])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 4-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid benzyl ester from step (a) above (300 mg, 0.677 mmol), acetamide (60 mg, 1 mmol, Aldrich), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (70 mg, 0.068 mmol, Strem Chemicals), 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (78 mg, 0.135 mmol, Aldrich) and cesium carbonate (331 mg, 1.01 mmol, Aldrich) in 1,4-dioxane (4 mL) was subjected to microwave irradiation at 170° C. for 0.5 h. The mixture was cooled to room temperature and was filtered. The filtrate was purified by silica gel column chromatography (2%-100% EtOAc/hexane) to give the title compound as a light-brown solid. MS (ESI, positive ion) m/z: 423 (M+1).