Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([SH:22])[CH:19]([SH:21])[CH3:20].[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:29]([CH:30]1[S:21][CH:19]([CH3:20])[CH2:18][S:22]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(S)CS
Reactant: O=CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC1CSC(Cc2ccccc2)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100 cc reaction flask equipped with reflux condenser, magnetic stirring bar and thermometer and hot plate equipped with magnetic stirring apparatus is placed 5 ml cyclohexane, 0.2 grams of para-toluenesulfonic acid and 5.4 grams (0.05 moles) of 1,2-propanedithiol. With stirring, over a period of 30 minutes, 6 grams (0.05 moles) of phenylacetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 8 hours. During the refluxing period, water of reaction is removed. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled on a Microvigreux column yielding the following three fractions:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH2:32][O:33][CH3:34])=[C:26](B(O)O)[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:31][CH2:32][O:33][CH3:34])=[C:24]([C:2]2[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COCOc1ccc(C(C)(C)C)cc1B(O)O
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1ccc(C(C)(C)C)cc1-c1ncc(C(F)(F)F)cn1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)pyrimidine (0.300 g, 1.64 mmol) in dimethoxyethane (9 mL) was added a 2 M aqueous solution of sodium carbonate (3.7 mL, 7.4 mmol) and (5-(tert-butyl)-2-(methoxymethoxy)phenyl)boronic acid (0.500 g, 2.14 mmol). The solution was degassed with nitrogen for five minutes and tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 16 hours. The cooled reaction mixture was partitioned between ethyl acetate (25 mL) and 1 M aqueous sodium hydroxide solution (25 mL), the organic phase separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 2-(5-(tert-butyl)-2-(methoxymethoxy)phenyl)-5-(trifluoromethyl)pyrimidine (0.25 g, 44% yield) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.Cl[C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.12 mmol) in DCM (2 mL) at 0° C. was added methyl 4-chloro-4-oxo-butanoate (19 mg, 15 μL, 0.12 mmol) followed by the addition of triethylamine (50 mg, 69 μL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The crude material was dissolved in DMSO and purified by reverse phase HPLC using 1-99% MeOH in H2O to obtain methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate, which was re-dissolved in THF (1.0 mL), treated with NaOH (996 μL of 2.5 M, 2.5 mmol) and stirred for 18 h at room temperature. The reaction mixture was then acidified with conc. HCl till pH7 and extracted with DCM. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified via reverse phase HPLC using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoic acid (5 mg, 11%). 1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.66 (d, J=4.1 Hz, 2H), 7.27 (dd, J=6.0, 3.1 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 4.34 (s, 1H), 4.27 (s, 1H), 3.84 (t, J=5.6 Hz, 2H), 2.85 (s, 1H), 2.80-2.65 (m, 3H), 2.56-2.47 (m, 2H). LC/MS m/z 393.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1)C)C1C=CC=CC=1.[CH2:35](O)C>[Pd]>[CH3:1][NH:8][CH:10]([CH3:35])[CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1
Reactant: CN(CCN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O)Cc1ccccc1
Reactant: CCO
Agent: [Pd]
Product: CNC(C)CN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O

Procedure:
4 g of 2-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a] [1,5]benzodiazepine-1,5-dione in 100 ml of ethanol containing 0.4 g of 5% palladium on charcoal is hydrogenated at 50 p.s.i. hydrogen pressure until 1 molar equivalent of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(OCC)(=O)C>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:16]=1[C:17]([NH:19][C:20]([NH:11][C:8]1[CH:7]=[N:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:12])[F:13])=[CH:10][CH:9]=1)=[O:21])=[O:18]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2,2,2-Trifluoroethoxy)-5-aminopyridine (0.5 gram) and 2,6-dichlorobenzoyl isocyanate (0.5 gram) were mixed in ethyl acetate, and the reaction mixture stirred overnight (about 18 hours) at room temperature. Solvent was removed by evaporation and the product residue crystallized from ethyl acetate-hexanes, yield 0.6 gram, m.p., 146°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccccc2F)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (105 mg, 0.48 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (74 mg, 0.54 mmol) and PS-DCC (501 mg, 1.28 mmol/g, 0.64 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (29.9 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (385 mg, 3.75 mmol/g, 1.44 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (60 mg, 63%) as a solid. MS: 294 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:35]([O:41]CC)(=O)[CH2:36][C:37]([CH3:39])=O>C(O)(=O)C>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[C:35](=[O:41])[CH2:36][C:37]([CH3:39])=[N:12]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Reactant: CCOC(=O)CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
Di-tert-butyl 1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 4b (2.70 g, 7.18 mmol) was dissolved in 100 mL of acetic acid followed by addition of 20 mL of trifluoroacetic acid. After the mixture was reacted at room temperature for 2 hours, ethyl acetoacetate (0.98 g, 7.54 mmol) was added. Then the mixture was heated to 100° C. and reacted for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The reaction mixture was neutralized by saturated sodium bicarbonate solution, and then was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(3,3-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 4c (1.0 g, yield 47.7%) as a light brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH:28]([C:29]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: O=C=Nc1ccccc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccccc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH2:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.N1C(C)=CC=CC=1C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]([F:16])([F:17])[F:15])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
Add methanesulfonyl chloride (16.42 mL, 0.21 mol) drop-wise to a mixture of (1S)-1-(4-bromophenyl)-2,2,2-trifluoroethanamine (49 g, 0.19 mol), 4-dimethylaminopyridine (1.18 g, 9.0 mmol), 2,6-lutidine (67 mL, 0.57 mol) in DCM (250 mL) at 0° C. Warm the mixture to ambient temperature and stir at that temperature for 20 hours. Dilute the reaction mixture with DCM (300 mL) and wash it sequentially with 2M HCl (2×200 mL), water (250 mL), then brine (250 mL). Collect the organic phase and dry over magnesium sulphate; filter; and concentrate under vacuum. Triturate the residue with hexane (200 mL) for 10 minutes, filter and dry the solid under vacuum to give the title compound as a pale brown solid (60 g, 93% yield, 98% ee). MS (m/z): 332 (M+1).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+]>>[CH3:17][C:16]1[C:15]([C:14]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][NH:11][CH:12]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1c[nH]cc1C
Yield: 71.1 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (8.55 g), ethyl crotonate (5.0 g) and potassium tert-butoxide (5.90 g), a procedure as in Reference Example 39 was performed to give the title compound as a pale-yellow solid (yield 4.77 g, 71%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O-:19])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O:19][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 1.5 h

Procedure:
To a solution of 38.1 mg of sodium (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 3 ml of DMF was added 0.021 ml of pivaloyloxymethyl iodide under the atmosphere of argon at −30° C., and the mixture was stirred for 1.5 hours. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with 20 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 3 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 35.8 mg of the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(O)C.O>[CH2:12]([NH:30][CH:11]1[O:4][C@@H:3]([CH3:2])[C@H:5]([OH:6])[C@@H:7]([OH:8])[C@H:9]1[OH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 50 h

Procedure:
9 g of L-rhamnose and 13.5 g of stearylamine in 100 ml of 2-propanol and 50 ml of water are stirred at 50° C. until a clear solution has resulted. After 50 hours at room temperature, the crystals are filtered off with suction, washed with ethanol and ether and dried in vacuo.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH3:22])[N:12]=1)=[O:10])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9]([C:11]1[C:15]([S:2]([OH:5])(=[O:4])=[O:3])=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:13]([CH3:22])[N:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(C)n1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nn(C)c(-c2ccccc2)c1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.5 ml of chlorosulfonic acid and 15 xl of dry chloroform was cooled to 0° C., and a solution of 11.5 g (0.05 mol) of 3-ethoxycarbonyl-1-methyl5-phenylpyrazole in 25 ml of dry chloroform was added dropwise thereinto. Then, the mixture was stirred at room temperature for one hour and under reflux for 3 hours. After the reaction, by evaporation of chloroform, there was obtained oily 3-ethoxycarbonyl-1-methyl-5-phenylpyrazole-4-sulfonic acid. As the next step, at room temperature 20.9 g of phosphorus pentachloride was added portionwise, followed by stirring at 90° to 100° C. for one hour. The reaction mixture was added into ice-water and extracted with ether to obtain 14.7 g of 3-ethoxycarbonyl-1-methyl-5-phenylpyrazole-4-sulfonylchloride. Then, the resultant sulfonylchloride was dissolved in 20 ml of acetone and 4.48 g of KHCO was added to the solution. After a solution of 2.7 g of aqueous ammonia (28 %) and 6.5 ml of acetone was added dropwise thereinto at room temperature, the mixture was heated at 50 to 60 ° C. for 30 minutes. After evaporation of acetone, water was added to the residue, whereby 12.9 g of the title compound was precipitated as a solid. Recrystallization from benzene gave 8.4 g of the product. m.p. 141°-144° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:33]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: C[C@H](O)C(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
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])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.[ClH:18].Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:18].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:24]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:31][CH2:30]1)=[O:17])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2ccc(C(=O)N3CCN(Cc4cc(OC)c(OC)c(OC)c4)CC3)cc2cc1OC
Yield: 80.2 %

Procedure:
Using 6,7-dimethoxy-2-naphthoic acid (0.7 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.1 g), triethylamine (1.25 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (1 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=2:3) and converted to the hydrochloride in ethyl acetate to give 1-(6,7-dimethoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.25 g) as colorless crystals, m.p. 235°-240° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH:9]=[O:10]
Reactant: OCc1cc(F)cc(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-fluorophenyl)methanol (378 mg, 1.86 mmol) was dissolved in DCM (10 ml), into which was added pyridinium chlorochromate (880 mg, 4.00 mmol). The mixture was stirred at rt under an atmosphere of nitrogen for 16 h. After that time, the reaction mixture was passed through a silica gel plug, eluting with DCM (250 ml) to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ=7.50-7.54 (m, 2H), 7.81-7.83 (m, 1H), 9.33 (d, J=2.0 Hz, 1H). HPLC: tR=3.27 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 72.5 °C
Yield: 83.4 %

Procedure:
The compound of Example 21 was also prepared according to the following method. To a solution of 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl)oxy]-2-fluorobenzoic acid (Preparation 265, 45.0 g, 131.52 mmol) in tetrahydrofuran (180 mL) at room temperature was added methansulphonamide (25.02 g, 263.04 mmol), N-ethyl-N-diisopropylpropan-2-amine (68.81 mL, 394.56 mmol) and 1-propanephosphonic acid cyclic anhydride (167.36 g, 263.04 mmol as a 50% solution in ethyl acetate) and the mixture stirred and heated at 70-75° C. for 16 hours. The reaction mixture was concentrated under reduced pressure at 45° C. and water added (450 mL), the resulting slurry was stirred for 30 minutes, filtered and dried. The crude product was dissolved in 2-propanol (1285 mL) at 85° C. and cooled slowly over 16 hours. The resulting slurry was filtered, washed with 2-propanol (2×40 mL) and dried to give the title compound as an off-white solid (46 g, 83%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[NH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
t-Butyl trans-4-aminomethylcyclohexylcarbamate (344 mg, 1.5 mmol) was dissolved in CH2Cl2 (7 mL) and cooled in an ice-bath. Triethylamine (0.21 mL, 1.5 mmol) was added, followed by benzyl chloroformate (0.22 mL, 1.5 mmol) dropwise. The mixture was stirred at rt under N2 for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water and brine, dried over Na2SO4, filtered, and concentrated to a white solid. This solid was dissolved in 10 mL of 4 N HCl-dioxane and stirred at rt for 10 min. The solvent was removed. The residue was dried under vacuum to give 350 mg of the desired product as a white solid (78%). MS 263.36 (M+H)+.