Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>CN(C=O)C.O>[Cl:1][C:2]1[N:3]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:7]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[N:8][C:9]=2[N:10]=1
Reactant: CC(C)CBr
Reactant: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Yield: 69.7 %

Procedure:
A mixture 2-chloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.27 mmol) and cesium carbonate (0.1 g, 0.30 mmol) was taken in DMF (2 ml) and isobutyl bromide (0.055 g, 0.41 mmol) was added drop wise. The reaction mixture was stirred and heated at 60° C. overnight, diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The residue was purified by column chromatography to provide 2-chloro-8-cyclopentyl-1-isobutyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.08 g, 69%) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3
Reactant: Cc1ccc(-c2cc3c4cc(C)ccc4[nH]c3n(C)c2=O)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3c4cc(C)ccc4n(C)c3n(C)c2=O)c(C)c1
Reaction time: 0.5 h

Procedure:
400 mg of 3-(2,4-dimethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one (compound 101) are dissolved in 10 ml of DMF. 31 mg of 95% NaH are added and the mixture is stirred at AT for 30 minutes. 380 μl of methyl iodide are added and the mixture is stirred at AT for 18 hours. It is evaporated to dryness. The residue is taken up in CH2Cl2 and the organic phase is washed with NaCl and then water, dried and evaporated. The residue is taken up in Et2O, filtration is carried out and drying is carried out. 300 mg of the expected product are obtained, M.p.=150° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH:19]([CH2:37][CH2:36][CH3:40])[C:20]([O:22][CH3:23])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1c(C)sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(CC)c2c1-c1ccc(C)cc1
Yield: 58.5 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.200 g; 0.566 mmol), LHMDS 1N in THF (0.635 mL; 0.635 mmol), 1-iodopropane (0.090 mL; 0.923 mmol) in DMF (8 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.131 g (59%) of the title compound as a white solid. ESI/APCI(+): 396 (M+H); 418 (M+Na).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([O-:13])=[O:12].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:11]([C:14]1[CH:15]=[C:16]([C:17]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:18])[CH:20]=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
Benzenesulphonamide (9.4 g, 60 mmol), 3-nitrobenzoic acid (10.0 g, 60 mmol), 4-dimethylaminopyridine (7.32 g, 60 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.48 g, 60 mmol) were stirred in anhydrous dichloromethane (400 ml) for 2 hours. The reaction mixture was extracted with 1M sodium hydroxide solution (300 ml), aqueous separated then re-acidified to pH=3 with 5M hydrochloric acid. 3-Nitro-(phenylsulphonylaminocarbonyl)benzene was isolated as a colourless solid (16.0 g, 87%), mp 186°-188° C.
Reaction SMILES: [C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]1=2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9]([NH:26][CH:27]2[CH2:36][CH2:35][CH2:34][C:33]3[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:42])[F:43])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]2=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (4.31 g, 11.56 mmol), trifluoro-methanesulfonic acid 5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Step D, 3.10 g, 10.51 mmol), HOBt (Aldrich, 1.28 g, 9.46 mmol), and CH2Cl2 (30 mL) was added EDC (Aldrich, 3.02 g, 15.76 mmol). The reaction was stirred at RT overnight and diluted with CH2Cl2 (100 mL). The organic phase was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (16-30% EtOAc-hexane) to afford the title compound as an off-white solid. MS (ESI): 651 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:7]=[CH:6]2)#[N:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:27][C:24]1[CH:25]=[CH:26][C:14]([O:13][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc2cc(C#N)ccc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(N)ccc1Oc1ccc2cc(C#N)ccc2c1

Procedure:
The compound (t-butyl 2-(6-cyano-2-naphthyloxy)-5-nitrobenzoate) (760 mg) obtained in a previous production example, iron powder (718 mg) and ammonium chloride (73 mg) were heated to reflux in ethanol:water (3:1, 30 ml) and reacted for 30 minutes. The insoluble portion was immediately filtered using celite, and the filtrate was concentrated. A saturated sodium bicarbonate solution was added to the obtained residue, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and then dried over magnesium sulfate, and the solvent was distilled off to obtain 736 mg of t-butyl 5-amino-2-(6-cyano-2-naphthyloxy)benzoate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](O)=[O:29]>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-chloro-6-methylbenzoic acid using the general procedures described in example 7 and was obtained as a white solid: mp 238-240° C. FAB-HRMS m/e calcd for C24H24ClN3O5 (M+H) 470.1483, found 470.1489.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:34][CH:33]=4)=[O:37])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reaction time: 2 h

Procedure:
At room temp. under nitrogen, to a solution of 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol) and diisopropyl(ethyl)amine (209 mg, 1.62 mmol) in acetonitrile (5 mL) is added 4-trifluoromethylphenyl isocyanate (197 mg, 0.97 mmol). The reaction mixture is stirred at room temp. for 2 h, concentrated, and the residue is purified by flash chromatography with CH2Cl2-MeOH to afford the title product.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1.C1N=C(N)SC=1.NC1C=CC=CN=1>C1COCC1>[OH:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(N)n1
Reactant: N#Cc1cnc(Cl)s1
Agent: Nc1ccccn1
Agent: Nc1nccs1
Agent: [H-]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cccc(CO)n2)s1
Temperature: 0 °C

Procedure:
An oven dried flask was charged with 6-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (1.27 g, 5.33 mmol) and 10 ml anhydrous THF. The solution was cooled to 0° C. and NaH (60% dispersion, 0.43 g, 11 mmol) was added. The reaction was warmed to room temperature and 2-chloro-thiazole-5-carbonitrile (0.924 g, 6.39 mmol) was added. The reaction was heated to 50° C. for 4 h. An additional 0.200 g (1.38 mmol) 2-chloro-thiazole-5-carbonitrile was added and the reaction was heated overnight. After a total of 18 h the reaction was cooled and quenched with water. The pH was adjusted to 7 with 1M HCl. The resulting precipitate was filtered and washed with water. Purification in two batches by flash column chromatography (suspended material on 5 g silica, eluted DCM to 97:3 DCM/MeOH) afforded a mixture of the aminothiazole and starting aminopyridine. This aminothiazole (0.710 g, 2.05 mmol) was dissolved in 10 mL anhydrous THF and the resulting solution was cooled to 0° C. HF-pyr, 2.4 mL, was added and the reaction was allowed to warm to room temperature. After 1 h the reaction was quenched by the addition of sat NaHCO3 (aq) and the THF was removed in vacuo. The resulting precipitate was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ 12.18 (s, 1H), 8.22 (s, 1H), 7.78 (t, 1H, J=7.6 Hz), 7.10 (d, 1H, J=7.5 Hz), 6.96 (d, 1H, J=8.2 Hz), 5.45 (t, 1H, J=5.7 Hz), 4.59 (d, 2H, J=5.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:11])[F:12]
Reactant: OCc1cnc(OCC(F)F)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol (0.87 g, 3.88 mmol, Step-3), phthalimide (0.63 g, 4.26 mmol), di-tert-butyl azodicarboxylate (2.11 mL, 4.65 mmol, ca. 2.2 mol/L in toluene) and triphenylphosphine (1.53 g, 5.81 mmol) in THF (26 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 to 3:1) to give 1.27 g (93% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:4][CH:5]=[C:6]([CH:8]=O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](Br)(Br)([Br:33])[Br:32]>ClCCl>[Br:32][C:31]([Br:33])=[CH:8][C:6]1[CH:7]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:4][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(C=C(Br)Br)co1
Reaction time: 1 h

Procedure:
A solution of 2-trimethylsilyl-4-furaldehyde (Compound 4, 1.0 g, 5.95 mmol) in dichloromethane (2 ml) was added to a solution of triphenylphosphine (3.9 g, 14.9 mmol) and carbon tetrabromide 2.46 g, 7.44 mmol) in dichloromethane (15 ml) at 0° under argon. After 1 hour, the mixture was extracted thoroughly with pentane. Evaporation of the pentane extracts gave an oil, which was flash chromatographed on silica using hexane. Fractions with Rf of about 0.52 on evaporation gave the title silylfuran as a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:23][CH:24]([CH3:26])[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH3+:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([O:23][CH:24]([CH3:25])[CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)OC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(C[NH3+])cc1)OC(C)C
Reaction time: 1 h

Procedure:
1.6 g of Ethyl 3-(4-{[(t-butoxycarbonyl)amino]methyl}-phenyl)-2-isopropoxypropanoate was dissolved in 10 ml of 4N hydrogen chloride-dioxane solution. After stirring was continued at room temperature for 1 hour, the solution was concentrated, to give 1.4 g of ethyl 3-[4-(ammoniomethyl)-phenyl]-2-isopropoxypropanoate hydrochloride. Next, 25 mg of the obtained ethyl 3-[4-(ammoniomethyl)phenyl]-2-isopropoxypropanoate chloride was dissolved in 0.8 ml of N,N-dimethylformamide which was saturated with carbon dioxide by adding dry ice, and 65 mg of cesium carbonate and 74 mg tetrabutylammonium iodide were added, and the mixture was stirred at room temperature for 30 minutes. Then 41 mg of 4-chlorobenzyl bromide was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was concentrated, and the residue was treated with 1.0 ml of ethanol and 0.2 ml of 5N sodium hydroxide, and the mixture was stirred at room temperature for 3 hours. Then the solution was neutralized with 2N hydrochloric acid, extracted with ethyl acetate, and the solvent was removed. The residue was purified by reverse-phase high performance liquid chromatography, to give 9.27 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](/[N:8]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1F
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 95.5 %

Procedure:
A suspension of 4-bromo-2-fluorobenzamide (0.929 g, 4.26 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.66 mL, 11.7 mmol) in a round bottom flask topped with a short path distillation head was heated to 100-100° C. The resulting solution was allowed to stir at this temperature for 3.5 hours, during which time the MeOH that was formed was collected from the distillation condenser. Heptane (5 mL) was added dropwise and the resulting suspension was cooled to 0-5° C. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford (E)-4-bromo-N-((dimethylamino)methylene)-2-fluorobenzamide (1.111 g, 96%) as an off-white solid which was carried on without further purification.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:14]N(C)CCCN=C=NCC.CO>ClCCl>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:14])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
N,N-Dimethylaminopyridine (7.6 mg, 0.06 mmol) was added to a mixture of 1H-indole-4-carboxylic acid (100 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol), and methanol (1 mL, 24.7 mmol) in dichloromethane (2 mL). The mixture was allowed to stir at room temperature overnight, then the solvent was evaporated and ethyl acetate (20 mL) was added. The solution was washed with 1 M HCl (2×15 mL), saturated sodium hydrogen carbonate (15 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated to give 1H-indole-4-carboxylic acid, methyl ester (85.4 mg, 79%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:42])[CH:40]=[CH2:41]>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:42])[CH:40]=[CH2:41]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cccc(C2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.071 mmol) in DCM (2 mL) was added pyridine (0.2 mL). Then acryloyl chloride (6 mg, 0.084 mmol) was added dropwise. The mixture was stirred at RT for 0.5 hr and partitioned between DCM (20 mL) and brine (20 mL). Organic layer was separated from aqueous layer, washed with brine (2×20 mL), dried over Na2SO4 and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 1.82 mg (5.38%) of 7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.34-7.26 (m, 4H), 7.10 (t, J=7.6 Hz, 1H), 7.04-6.95 (m, 4H), 6.84 (d, J=7.6 Hz, 1H), 6.39-6.25 (m, 2H), 5.69 (dd, J=2.4, 9.6 Hz, 1H), 5.47-5.44 (m, 1H), 3.38-3.31 (m, 1H), 3.22-3.12 (m, 1H), 2.52-2.42 (m, 1H), 2.23-2.17 (m, 1H). MS (ESI) m/e [M+1]+ 480.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=1[Cl:21])=[O:13]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1Cl)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)cc1Cl
Yield: 18.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2,4-dichloroaniline (1.89 g, 11.7 mmol) in 15 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate, ethanol and methanol (1:1:1) and filtered to yield 0.64 g of the title compound, mp 227-228° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[Br:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>ClC1C=CC=CC=1>[Br:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[S:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(=O)CSc1ccc(Br)c(OC)c1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1
Product: CCOC(=O)c1csc2cc(OC)c(Br)cc12
Yield: 27.1 %

Procedure:
Ethyl 3-(3-methoxy-4-bromophenylthio)-2-oxopropanoate (D3) (3.7 g, 11 mmoles) in chlorobenzene (25 ml) was treated with phosphorus pentoxide (11.1 g, 78 mmoles) and 85% phosphoric acid (5.5 ml). The mixture was heated under reflux for 6 hrs. The mixture was allowed to cool and then partitioned between water (150 ml) and dichloromethane. The organics were washed several times with water then dried (Na2SO4). Evaporation to dryness followed by flash chromatography on TLC silica gel eluting with dichloromethane/60-80 petrol-ether 1:1 gave the title compound (D4) (0.94 g, 27%).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 0 °C

Procedure:
Sodium metal (8.68 g, 378 mmol) was added to methanol (350 mL) pre-cooled to 0° C. After the sodium completely dissolved, 2-chloro-5-nitro-6-methylpyridine (40.78 g, 236 mmol) was slowly added as a solid. The reaction mixture was heated at reflux temperature overnight, then poured into ice-water. The product was filtered and dried in vacuo overnight to give 29.39 grams of the title compound. (73%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:16])=O.CN(C=O)C>ClCCl>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:16])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexyl-carboxylic acid (10.7 g, 54.3 mmol) and thionylchloride (10 mL, 138 mmol) in 100 mL dichloromethane with 200 μL DMF was refluxed for 2 h. The mixture was concentrated i.vac. and triturated with dichloromethane. The residue was reacted without further purification.