Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22]4[C:31]([CH3:32])=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].ClCCl.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22]4[C:31]([CH3:32])=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:21]=[C:8]3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(C3=CCCC3)cc(NC3CCOCC3)n2n1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3CCCC3)cc(NC3CCOCC3)n2n1
Reaction time: 3 h

Procedure:
A suspension of 5-cyclopent-1-en-1-yl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (30 mg, 0.0703 mmol) and palladium on carbon (5%, 30 mg) in dichloromethane (2.0 mL) and methanol (2.0 mL) was stirred for 3 h under hydrogen atmosphere. Then reaction mixture was filtrated with chloroform, and the filtrate was concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 1:1) to give 5-cyclopentyl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 1.012 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.67-1.95 (8H, m), 2.08-2.20 (4H, m), 3.05 (3H, s), 3.11-3.23 (1H, m), 3.60 (2H, ddd, J=11.8, 11.8, 2.4 Hz), 3.74-3.85 (1H, m), 4.10 (2H, ddd, J=11.5, 3.3, 3.3 Hz), 5.94 (1H, s), 6.32 (1H, d, J=7.9 Hz), 7.02 (1H, s), 7.71-7.79 (2H, m), 8.04-8.08 (1H, m), 8.16-8.20 (1H, m).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[CH2:7]([SH:9])[CH3:8]>>[CH2:7]([S:9][CH2:3][CH2:2][CH2:1][N:4]=[C:5]=[O:6])[CH3:8]
Reactant: CCS
Reactant: C=CCN=C=O
Product: CCSCCCN=C=O

Procedure:
A mixture of 16.6 grams (0.2 mole) of allyl isocyanate and 12.4 grams (0.2 mole) of ethanethiol is irradiated at -30° C for 24 hours in the manner described in Example 1 to yield the olefinic adduct, i.e. 3-ethylthiopropyl isocyanate as the major product.
Reaction SMILES: CS(O[CH2:6]/[CH:7]=[CH:8]\[CH2:9]OS(C)(=O)=O)(=O)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:15][C:16]1[CH:17]=[C:18]([N:19]2[CH2:9][CH:8]=[CH:7][CH2:6]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)OC/C=C\COS(C)(=O)=O
Reactant: Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(N2CC=CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
Then, a mixture of 15 g of the cis-1,4-bis(methanesulfonyloxy)-2-butene, 10 g of 3-bromoaniline, 24 g of anhydrous potassium carbonate and 70 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 5% ethyl acetate/hexane, to give 6.6 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:9].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30]([C:29]1[C:28]([CH3:35])=[N:1][C:2]2[C:3]([C:25]=1[NH2:26])=[C:4]([O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:9])[CH:22]=[CH:23][CH:24]=2)=[O:31])[CH3:34]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cccc(CNC(=O)C(C)(C)COc2cccc(N)c2C#N)c1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3cccc(OC)c3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide (Example 46b) and ethyl 3-oxobutanoate as a yellow solid (42%). MS 466 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.I([Cl:28])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[C:12]([OH:15])=[C:13]([Cl:28])[CH:14]=1
Reactant: O=I(=O)Cl
Reactant: COc1ccc(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)cc(Cl)c1O
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a stirred solution of 3,5-dibromo-4-(3-isopropyl-4-methoxyphenoxy)phenylacetic acid (1.5 g, 3.4 mmol) in acetic acid (40 mL) at room temperature was added benzyltrimethylammonium tetrachloroiodate (1.42 g, 3.4 mmol). The reaction mixture was stirred for one hour and was filtered. The filtrate was concentrated, and the product was extracted with ethyl acetate, washed with saturated NaHCO3 (aq), NaCl (aq), and dried over MgSO4 and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol/acetic acid 98:2:0.3) to give 802 mg (50%) of 3,5-dibromo-4-(3-chloro-4-hydroxy-5-isopropylphenoxy)phenylacetic acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2.[Cl:26][CH:27]=[CH:28][CH2:29]Cl>CN(C=O)C>[Br:3][C:4]1[C:5]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:29][CH:28]=[CH:27][Cl:26])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)c(Br)c2c1
Reactant: ClC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccc(N(CC=CCl)C(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
NaH (57 mg, 1.42 mmol, 60% in oil) was added to a solution of bromide 180 (450 mg, 1.18 mmol) in DMF (5 mL) at 0° C. 1,3-Dichloropropene (260 mg, 2.37 mmol) was added and the mixture was allowed to warm to room temperature over 1 h, then concentrated under reduced pressure CH2Cl2 and water were added and the organic phase was washed with water (×2), brine (×2), dried, and filtered through silica gel to give methyl 8-bromo-7-[(tert-butoxycarbonyl)(3-chloro-2-propen-1-yl)amino]-2-naphthoate (181) (520 mg, 97%) as a yellow oil; 1H NMR (CDCl3) (mixture of rotamers and E and Z forms) δ 9.07 (s, 10H), 8.18-8.08 (m, 1H), 7.93-7.78 (m, 2H), 7.42-7.32 (m, 1H), 6.15-5.98 (m, 2H), 4.01 (s, 3H), 4.63-4.48 (m, 2H), 1.26, 1.24 (2 s, 9H). HRMS (FAB) calcd. for C20H2179Br35ClNO4 (MH+) m/z 454.0421, found 454.0421.
Reaction SMILES: C([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=O)=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])(C)(C)C.[ClH:25].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl.O1CCOCC1>[ClH:25].[N+:21]([C:8]1[CH:9]=[C:10]([CH2:13][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]=[CH:12][C:7]=1[C:6]([OH:24])=[O:5])([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCCCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-Nitro-4-(piperidine-1-carbonyl)-benzoic acid tert-butyl ester (1.87 mmol) was dissolved in dry THF and added drop-wise to 3.7 mL of borane tetrahydrofuran complex 1.0 M solution, at room temperature, under nitrogen, with stirring. The reaction was then refluxed for six hours, cooled to room temperature and treated carefully with 2N HCl (10 mL) After stirring for 15 minutes, solid K2CO3 was added in portions (1.75 g). The mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried over sodium sulphate and evaporated leaving an oil that by HPLC-MS analysis resulted a 4:6 mixture of the tertiary amine and the corresponding borane complex. The mixture was dissolved in DCM (1 mL) and treated with 4N HCl in dioxane (7 mL). After 4 days at room temperature, an off white was formed which was filtered, washed with dioxane (5 mL) and dried at 50° C. under vacuum. 0.40 g of title compound were obtained in 70% overall yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH2:12][CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 86.1 %

Procedure:
Using 4-bromo-2-fluorobenzoic acid (1.08 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.01 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.72 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44][CH2:45][O:46][CH2:47]Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][O:20][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: COCCOCCl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCOC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 250 mg, 0.57 mmol), diisopropyl ethyl amine (238 μL, 1.37 mmol) and 2-methoxyethoxymethyl chloride (MEMCI) (78 μL, 0.68 mmol) were mixed in dry DMF (5 mL) and stirred at room temperature overnight. More diisopropyl ethylamine (250 μL, 1.44 mmol) and MEMCl (100 μL, 0.88 mmol) were added and it was stirred for another 6 hours. Again MEMCl (90 μL, 0.79 mmol) was added and it was stirred overnight. The solvent was evaporated under reduced pressure. Chromatography on silica gel with acetone/hexanes 3:1 and precipitation from dichloromethane/hexanes gave the product as off-white solid (261 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH2:3][OH:4].[N:17]#[C:18]Br>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:18]([NH2:17])=[N:1]2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCS(=O)(=O)c1ccc(F)cc1
Product: NC1=N[C@@H](CCS(=O)(=O)c2ccc(F)cc2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(4-fluoro-phenylsulfonyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-fluoro-phenylsulfonyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Colourless oil. MS (ISP): 273.1 ([M+H]+).
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.N1C=CC(=O)NC1=O.[N:18]([O-])=[O:19].[Na+]>C(O)(=O)C.O>[N:18]([C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][CH:2]=1)=[O:19]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: O=c1cc[nH]c(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c[nH]c(=O)[nH]c1=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 132 %

Procedure:
1-Propyl, 3-cyclopropyl, 6-aminouracil (2) (12.8 g, 61.2 mmol ) was dissolved in acetic acid (25 ml) in 200 ml of water and the mixture was cooled to 10° C. To the uracil solution, NaNO2 (7.6 g, 110.1 mmol ) in 50 ml of water was added dropwise at 10° C. The mixture was stirred at 10° C. for 30 min and then at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in the mixture of absolute ethanol and CH2Cl2 (1:1) and boiled for 20 min. The hot mixture was filtered through a layer of Celite 545 to remove the insoluble inorganic salts. The mother liquid was evaporated under reduced pressured to remove the solvent to give 1-propyl, 3-cyclopropyl, 6-amino, 5-nitrosouracil (4) (11.4 g, 78%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[CH3:43][S:44]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=1)[CH3:25])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
4-(9-Hydroxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (435 mg, 0.89 mmol) was dissolved in dichloromethane (30 ml), to which were added triethylamine (0.62 ml, 4.47 mmol) and methanesulfonyl chloride (0.34 ml, 4.47 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate-7:3) to give the title compound (0.49 g, yield 97%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C@H:6]([CH3:10])[C@H:7]([OH:9])[CH3:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>ClCCl>[CH3:18][S:19]([O:9][C@@H:7]([C@H:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:10])[CH3:8])(=[O:21])=[O:20]
Reactant: CCCCO[C@H](C)[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCO[C@H](C)[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
1.00 g of (2R,3R)-3-butoxy-2-butanol and 0.83 g of triethylamine were dissolved in 10 ml of dichloromethane. Thereto was dropwise added 0.94 g of methanesulfonyl chloride with ice-cooling. The mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with dilute hydrochloric acid and an aqueous sodium bicarbonate solution in this order, and then dried and concentrated under reduced pressure. The residue was subjected to Kugel-rohr distillation (1 mmHg) to obtain 1.30 g of (2R,3R)-3-butoxy-2-butyl methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13]N=1)[CH2:7][C:8]#C)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1>[N:16]1[CH:15]=[CH:14][CH:13]=[C:8]2[CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:11]=12
Reactant: C#CCN(Cc1ncccn1)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1Cc2cccnc2C1

Procedure:
7.7 g (35 mmol) of 2-(N-ethoxycarbonyl-N-propargyl-aminomethyl)-pyrimidine are refluxed for 40 hours in 150 ml of xylene. The mixture is concentrated, and the residue is recrystallised from ligroin.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:10][NH:11][C:12](=[NH:20])[CH:13](OCC)OCC.ClC1C=C2C(=CC=1Cl)C(N)=NC=C2>>[Cl:6][C:7]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:9]2[C:8]=1[CH:13]=[C:12]([NH2:20])[N:11]=[CH:10]2
Reactant: CCOC(OCC)C(=N)NCc1ccc(Cl)c(Cl)c1
Agent: Nc1nccc2cc(Cl)c(Cl)cc12
Agent: O=S(=O)(O)O
Product: Nc1cc2c(Cl)c(Cl)ccc2cn1
Temperature: 40 °C
Yield: 85.5 %

Procedure:
To sulfuric acid (4 mL, 75 mmol) was added N-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2 g, 6.6 mmol) at room temperature. The reaction was heated to 40° C. for 49 hours. TLC and LC/MS indicated the presence of product. The reaction was cooled to room temperature and quenched with aq. NaOH (˜15 M) until the reaction mixture was ˜pH 7. The crude product was extracted with ethyl acetate (2×50 mL) and the organics were dried with MgSO4, filtered, and concentrated in vacuo to yield the product. The crude product was purified by chromatography (Biotage: 100% ethyl acetate to [90/10% ethyl acetate/MeOH]) to yield approximately a 1:1 mixture of regioisomers 6,7-dichloroisoquinolin-1-amine and 5,6-dichloroisoquinolin-3-amine (1.2 g, 5.64 mmol, 86.0% yield) as a dark yellow powder. The regioisomers were carried on without separation. 1H NMR: 1H NMR (500 MHz, DMSO-D6) δ ppm 8.90 (s, 1 H), 8.83 (s, 1 H), 8.12 (s, 1 H), 7.89 (s, 1 H), 7.84 (d, J=8.54 Hz, 1 H), 7.28 (d, J=8.85 Hz, 1 H), 6.83 (s, 1 H), 6.58 (s, 1 H), 6.48 (s, 2 H), 6.25 (s, 2 H). MS (LC/MS) R.T.=1.59; [M+H]+=213.0.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]1[CH2:37][CH:36]([OH:38])[CH2:35][CH:34]1[CH:39]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[O:40][CH:41]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)=[O:32]>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:41]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[O:40][CH:39]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:34]2[CH2:35][CH:36]([OH:38])[CH2:37][N:33]2[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:1](=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:43][CH:44]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Yield: 41 %

Procedure:
Using the above described procedure, docosanoic acid 101h (3.41 g, 10 mmol) was coupled with the amine 100 and after work-up and column purification the pure amide was isolated as a foam (3.5 g, 41%). 1H NMR (DMSO-d6, 400 MHz) δ=7.69 (m, 1H), 7.32-6.80 (m, 13H), 4.98 (d, J=3.90 Hz, 0.7H), 4.88 (d, J=3.90 Hz, 0.3H), 4.40-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.13 (m, 2H), 3.10-2.87 (m, 3H), 2.20-1.80 (m, 6H), 1.50-1.08 (m, 44H), 0.81 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.78, 170.89, 170.79, 162.30, 162.25, 158.09, 157.97, 145.08, 144.73, 135.86, 135.70, 135.45, 135.40, 129.59, 129.53, 127.82, 127.72, 127.56, 126.69, 126.52, 113.14, 113.05, 85.78, 85.10, 68.58, 67.44, 65.19, 63.32, 55.60, 55.05, 54.96, 54.93, 38.22, 38.01, 36.30, 35.76, 35.43, 34.16, 32.53, 31.35, 30.74, 29.09, 28.87, 28.78, 28.73, 26.20, 25.35, 24.13, 22.13, 13.88.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[C:15]=1[C:16]#[N:17]
Reactant: OCc1ccc(F)c(F)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,4-Difluorobenzyl alcohol (1.47 g; 10.1 mmol) was added to a cooled (0° C.) slurry of sodium hydride (0.414 g; 10.3 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylformamide, stirred for 3 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.47 grams of 2-fluoro-6-(3,4-difluorophenylmethoxy)benzonitrile.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:31])([CH3:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[S:13][C:12]([O:14]C(C)C)=[N:11][C:10]=2[CH:18]=1)(C)(C)C>C(O)=O>[CH3:31][C:22]([NH:21][CH2:20][C@@H:19]([C:8]1[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]=2[CH:18]=[C:6]([OH:5])[CH:7]=1)[OH:32])([CH3:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H](O)CNC(C)(C)Cc3ccccc3)c2s1
Solvent: O=CO
Product: CC(C)(Cc1ccccc1)NC[C@H](O)c1cc(O)cc2[nH]c(=O)sc12

Procedure:
(R)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-(1,1-dimethyl-2-phenyl-ethylamino)-ethanol (40 mg) is stirred in formic acid (2 ml) for 72 hours. The formic acid is removed in vacuo and the title compound is obtained by reversed phase column chromatography using a Jones Flashmaster Personal™ flash chromatography system (ISOLUTE FLASH C18, gradient elution AcCN/water 0 to 50%). MS (ES+) m/e 359.26 (MH+) LCT57144
Reaction SMILES: C([C:5]([N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:15][C:14]1=[O:30])([CH2:9][CH2:10][O:11][CH3:12])[C:6]([OH:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]([C:16]2[C:17]([O:19][CH3:20])=[CH:18][N:13]([CH:5]([CH2:9][CH2:10][O:11][CH3:12])[C:6]([OH:8])=[O:7])[C:14](=[O:30])[CH:15]=2)[CH:26]=1
Reactant: COCCC(C(=O)O)(n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
1.99 g (4.60 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) in 46 ml of dichloromethane and 13.3 ml (172 mmol) of TFA were reacted according to General Method 6A. Yield: 1.58 g (91% of theory)
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:10])=[CH:28][CH:27]=1
Reactant: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)NCCCCc1cccnc1
Yield: 81.4 %

Procedure:
As in Example 134. a solution of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (6.35 g) and 3-pyridinebutanamine (2.7 g) in tetrahydrofuran (75 mL) was stirred for 2 hours at 25° C. and was worked up in the usual fashion. The crude material was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to give 5.3 g of (E)-5,5-bis(4-chlorophenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 146°-147° C.