Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[Cl:11])=[N:1][C:2]=2[CH:6]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (100 mg), 2-chlorobenzoylchloride (57 μL), N,N-dimethylpyridin-4-amine (55 mg), pyridine (1.0 mL) and N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1.5 hr. The reaction system was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution was added to the residue, and the mixture was heated to 120° C. After 1 hr, insoluble material was removed by filtration, and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by filtration and washed with water to give the title compound (120 mg) as a dark orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][CH2:18][O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:24][CH2:23]1)([O:19][CH2:18][CH3:17])=[O:21]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a reaction vessel equipped with stirrer, thermometer and drying tube was charged 60 ml. of isoamyl alcohol, 10 g. (0.042 mole) of 4-amino-2-chloro-6,7-dimethoxyquinazoline (prepared as described in U.S. Pat. No. 3,511,836) and 7.3 g. (0.047 mole) ethyl-N-piperazinocarboxylate (Aldrich Chemical Co.). The mixture was heated at 100° C. for 3 hours and allowed to stand overnight at room temperature. The mixture was diluted with 120 ml. of isoamyl alcohol and filtered to obtain 14.3 g. (94%) of the hydrochloride salt of the title compound, which melted sharply at 295° C.
Reaction SMILES: C[Si]([C:5]1[NH:10][C:9](=[O:11])[N:8]([Si](C)(C)C)[C:7](=[O:16])[C:6]=1[F:17])(C)C.FC1C(=O)NC(=O)NC=1.[CH2:27]([CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[CH3:28].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO.C(O)CO>[OH:33][CH2:32][CH2:31][O:30][CH:29]([N:10]1[CH:5]=[C:6]([F:17])[C:7](=[O:16])[NH:8][C:9]1=[O:11])[CH2:27][CH3:28]
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: CCC1OCCO1
Agent: O=C([O-])O
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: OCCO
Product: CCC(OCCO)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bis(trimethylsilyl)-5-fluorouracil which had been prepared by treating 5-fluorouracil (10 g) as in Example 1 was dissolved in chloroform (20 ml). Separately prepared 2-ethyl-1,3-dioxolan (15 ml) from propionyldehyde (25 ml) and ethylene glycol (25 ml) was added to the above solution. Then, to the mixture was added dropwise a solution of anhydrous stannic chloride (6 ml) in chloroform (15 ml) under cooling in an ice bath for one hour. Following stirring at room temperature for one hour, the reaction mixture was poured into methanol (100 ml) containing sodium bicarbonate (30 g) and, after removing the resulting precipitate by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in water (10 ml), purified by column chromatography with use of Amberlite XAD-4 (Rohm and Haas Co.), and then treated with benzene to give 8.7 of crystalline 1-[1-(2-hydroxyethoxy)propyl]-5-fluorouracil.
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:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[NH:12][N:11]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[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:18]2[C:13](=[CH:14][C:15]([C:19]([NH:25][CH:22]3[CH2:24][CH2:23]3)=[O:20])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (200 mg, 0.719 mmol) in DMF (30 mL) was added cyclopropylamine (98 mg, 0.719 mmol), HATU (0.719 mmol, 273 mg), and triethylamine (0.726 mmol, 0.1 mL). This solution was allowed to stir at room temperature overnight The reaction was worked up via aqueous wash and extraction with ethyl acetate (3×50 mL). The organic layer was then dried with MgSO4, filtered and concentrated to yield a dark oil. Flash column chromatography (30-70% Ethyl Acetate/Petroleum Ether) afforded the 3-(1H-benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide as a yellow solid. (0.130 g, 57%) 1H NMR (DMSO d) δ 13.88 (1H, s), 8.63 (1H, m), 8.51 (1H, d, J=8.5 Hz), 8.09 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.63 (2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m). MS (APCI positive) 318.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
6-Chloro-2-pyridinecarboxylic acid (available from Fluorochem, 2540 mg, 16.1 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (6130 mg, 16.1 mmol) were dissolved in DMF (40 ml) and DIPEA (8.44 ml) was added. The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (2000 mg, 8.06 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to ˜15 ml which was added to 4×50 g aminopropyl cartridges which had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The fractions were combined and the solvent was removed in vacuo to give a brown oil which was purified by chromatography on silica gel (2×100 g cartridges) eluting with 0-25% MeOH in dichloromethane over 40 mins. Appropriate fractions were combined and the solvent was removed in vacuo to give the title compound (809 mg) as an orange solid.
Reaction SMILES: [P:1]([O-:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH2:18]=[O:19]>>[OH:19][CH2:18][P:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)OP([O-])OC(C)C
Reactant: C=O
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(CO)OC(C)C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A mixture of 33.2 g (0.20 mol) of diisopropyl phosphite, 2.8 ml (0.02 mol) of triethylamine, and 6.0 g (0.20 mol) of paraformaldehyde, was immersed in a 100° C. oil bath and then heated between 100°-120° C. for 45 minutes under nitrogen. An exotherm occurred within 10 minutes and all of the paraformaldehyde dissolved rapidly. The triethylamine was removed at reduced pressure, and the residue was bulb-to-bulb distilled in four portions to provide a total of 35.17 g (91%) of title compound as a colorless oil. TLC Silica gel (5:95 CH3OH:CH2Cl2) Rf =0.17
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:5].[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[ClH:17].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:3][CH:2]([OH:1])[CH:4]([O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:13][C:14](=[O:16])[CH3:15])[CH3:5])[CH2:24]2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(OC2CCNC2)cc1
Reactant: CC(=O)Nc1ccccc1OC(C)C1CO1
Product: CC(=O)Nc1ccccc1OC(C)C(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Product: Cl
Yield: 100 %

Procedure:
The title compound (230 mg, 100%) was prepared from N-[2-(1-oxiranylethoxy)phenyl]acetamide diasteromer 2 (123 mg, 0.557 mmol) and 3-(4-chlorophenoxy)pyrrolidine (100 mg, 0.506 mmol) analogously to that described in Example 1 (iii).
Reaction SMILES: C=C.[Cl:3]Cl.[Cl:5][CH2:6][CH2:7][Cl:8]>[Fe](Cl)(Cl)Cl>[Cl:3][CH:7]([Cl:8])[CH3:6].[Cl:5][CH:6]([Cl:3])[CH2:7][Cl:8]
Reactant: ClCl
Reactant: ClCCCl
Agent: Cl[Fe](Cl)Cl
Agent: C=C
Product: CC(Cl)Cl
Product: ClCC(Cl)Cl

Procedure:
The procedure was as described in Example 5 but 2155 g 1,2-dichloroethane containing 1.7 g dissolved iron(III)chloride was introduced into the reactor. The solution contained 0.083 weight % FeCl3, determined colorimetrically. The quantities of ethylene and chlorine introduced in the presence of air underwent reaction inside the reactor to give crude dichloroethane containing 0.12 weight % 1,1,2-trichloroethane.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[NH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[H-].[Na+].[N+:20](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>O1CCOCC1.CN(C)C=O>[NH2:20][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:17]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Temperature: 60 °C
Yield: 63.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23a, 2.0 g, 8.92 mmol) in dioxane (7.5 mL) and dimethylformamide (7.5 mL) is added NaH (60% dispersion in oil, 428 mg, 10.7 mmol). The solution is heated to 60° C. for 10 minutes and cooled to room temperature. To the cooled solution is added O-(2,4-dinitrophenyl)hydroxylamine (1.77 g, 8.92 mmol), and the solution is heated to 80° C. for 30 minutes. The resulting red solution is cooled to room temperature, poured over crushed ice, and extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered, and the solvent removed under reduced pressure. The resulting solid is triturated with Et2O and air dried to afford 1.44 g of the title compound. MS CI: m/z 254 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49])/[C:40](=[N:42]/O)/[NH2:41]>CN(C=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([C:40]2[N:42]=[C:18]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:15]=3[CH2:16][CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[O:20][N:41]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)O)C1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)n2)cc1Cl
Temperature: 140 °C
Yield: 68.8 %

Procedure:
To a slurry of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (0.380 g, 1.371 mmol) in DMF (1.662 ml) was added EDC (0.263 g, 1.371 mmol) followed by HOBT hydrate. After about 1 h a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.285 g, 1.246 mmol) in DMF (0.831 ml) was added and the reaction mixture was heated to 140° C. for about 1 hr. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel to provide tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.403 g, 69%) as a colorless oil. LCMS (Table 1, Method c) Rt=3.43 min, m/z 471 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:3]([O:13][CH3:14])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1OC
Yield: 73.2 %

Procedure:
To a solution of methyl 3-amino-5-chloro-2-methoxybenzoate (440 mg, 2 mmol) in 1,2-dichloroethane (8 ml) at temperature under nitrogen was added oxan-4-one (0.38 ml, 4.0 mmol) followed by acetic acid (0.7 ml, 12 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (1.3 g, 6.1 mmol) at room temperature. After stirring for 23 hours deionized water (16 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×16 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 439 mg (72%) of the title compound as a white solid. LC-MS 97%, m/z=300.3/302.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.06 (1H, d, J=2.52 Hz), 6.73 (1H, d, J=2.52 Hz), 4.38-4.45 (1H, m), 4.02 (2H, dt, J=11.78, 3.49 Hz), 3.91 (3H, s), 3.81 (3H, s), 3.54 (2H, td, J=11.47, 2.13 Hz), 3.40-3.50 (1H, m), 2.03 (2H, br. d, J=13.70 Hz), 1.48-1.55 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.[C:20]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:20])[C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: CC[C@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5,7-dihydropteridin-6-one 41e (2.80 g, 10 mmol) was dissolved in 50 mL of acetone followed by the addition of methyl p-toluenesulfonate (2.80 g, 15 mmol) and potassium carbonate (2.76 g, 20 mmol) successively, stirred for 12 hours. The resulting solution was added with 50 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure, The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound (7S)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (2.50 g, yield: 85.0%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([OH:19])(=O)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1>CN(C)C=O>[ClH:3].[Cl:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([Cl:3])(=[O:19])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1cccc2c(Cl)nccc12
Solvent: CN(C)C=O
Product: Cl
Product: O=S(=O)(Cl)c1cccc2c(Cl)nccc12

Procedure:
To 40 ml of thionyl chloride were added 2.93 g of 1-chloro-5-isoquinolinesulfonic acid as obtained in Example 1 and 0.4 ml of N,N-dimethylformamide. Then, the resulting mixture was refluxed while heating at 80° to 85° C. for 2 hours, followed by removal of the thionyl chloride under reduced pressure. Subsequently, 10 ml of dichloromethane was added to the reaction mixture to precipitate crystals, followed by separation of the crystals by filtration. The crystals thus obtained were washed with 10 ml of dichloromethane, and then dried under reduced pressure to obtain 3.06 g of 1-chloro-5-isoquinolinesulfonyl chloride hydrochloride. The compound was analyzed to give the following data.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[CH2:5][O:6]C(=O)C1C=CC=CC=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:26][CH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[CH:5]=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(COC(=O)c2ccccc2)c1
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C=O)cc(CBr)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A mixture of benzoic acid 3,5-dimethyl-benzyl ester (24 g, 0.1M) and NBS (39.16 g, 0.22M) in carbon tetrachloride (200 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give 21 g of crude 3-bromomethyl-5-methyl-benzaldehyde.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (3S,4S)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (for a synthesis see WO2006002047 preparation 24(c), (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate E1 isomer) (1 g, 2.85 mmol) in DCM (50 ml) was added trifluoracetic acid (50 ml) and stirred for 2 h. The reaction mixture was concentrated and placed under high vacuum for 3 h. To the TFA salt dissolved in DCM (50 ml) was added MP-carbonate resin (4 g; 11.4 mmol) and stirred overnight. The reaction mixture was filtered and concentrated to provide the title compound as a pale yellow oil (840 mg, 100%)
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:25][C:26]([NH:28][C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]2)=[O:27])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:16]=[C:11]([CH:10]([NH:25][C:26]([NH:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:33][CH2:34]2)=[O:27])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=2)[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: COC(=O)c1ccc(C(NC(=O)N[C@H]2CC[C@H](C(C)(C)C)CC2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](NC(=O)NC(c2ccc(C(=O)O)cc2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Trans-4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoic acid methyl ester (1.4 g) was suspended in absolute ethanol (20 mL), sodium hydroxide (2N, 11 mL) was added and the reaction mixture was gently refluxed for 2 hours. The ethanol was removed in vacuo, additional water (40 mL) was added, pH was adjusted with hydrochloride (4 N) to acidic reaction and then ethyl acetate (200 mL) was added. The organic phase was isolated, washed with water (4×50 mL), dried with magnesium sulphate, filtered and evaporated in vacuo, affording 1.1 g (85%) trans-4-[1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-tert-butylcyclohexyl)ureidomethyl]benzoic acid as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[Li].O>O.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nc3scnc23)cc1OC
Reaction time: 0.15 h
Yield: 64.8 %

Procedure:
A solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoate (190 mg, 0.255 mmol) and LiOH.H2O (149 mg, 3.55 mmol) in 2 mL of water, 10 mL of methanol and 15 mL of THF was stirred at room temperature for 2 hours. The solvent was evaporated after the solution was acidified by 2N HCl to pH=2 and the residue was dissolved in 50 mL of THF, filtered to remove the salts. The filtrate was evaporated and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 25% acetonitrile/75% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (86 mg, 46.5%) as a solid. 1H NMR (300 MHz, DMSO): δ 9.63 (s, 1H), 8.36-8.79 (m, 2H), 8.02-7.88 (m, 5H), 7.60-7.50 (m, 1H), 6.93 (d, 1H, J=8.7 Hz), 4.61-4.59 (m, 1H), 3.95-3.66 (m, 10H), 2.28-2.10 (m, 2H). LC-MS: 521 [M+H]+; 518.8 [M−H]−, tR=1.36 min. HPLC: 99.85% at 214 nm, 99.84% at 254 nm, tR=4.67 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:5][CH3:6])[CH3:4].[CH:7]([O:10][CH3:11])=[CH:8]C.[CH2:12](N(CC)CC)C>B(F)(F)F.CCOCC>[CH3:1][O:2][CH:3]([O:5][CH3:6])[CH:4]([CH3:12])[CH:7]([O:10][CH3:11])[CH3:8]
Reactant: CC=COC
Reactant: CCN(CC)CC
Reactant: COC(C)OC
Agent: FB(F)F
Solvent: CCOCC
Product: COC(C)C(C)C(OC)OC
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
1035 g (11 mol) of acetaldehyde dimethyl acetal [purity according to gas chromoaography (GC): 96.5%] and 3.4 g (3 ml, 24 mmol, 0.22 mol %) of boron trifluoride etherate were placed under argon in a 2 1 two-necked round flask fitted with a magnetic stirrer, a thermometer and a dropping funnel. 530 g (7.35 mol) of methyl (1-propenyl) ether were added dropwise to the mixture within 2 hours at between 30 and 40° C. with occasional cooling (the reaction was exothermic). After completion of the addition the mixture was stirred for a further 30 minutes at 30° C., then cooled to room temperature. 3 ml of triethylamine were added thereto, the mixture was stirred for 15 minutes and suction filtered. The excess acetaldehyde dimethyl acetal was then distilled off on a Raschig column (50×3 cm) at normal pressure and the residue was fractionated on the same column. This gave at a pressure of 50 mbar a 1st fraction (b.p. 81.5-83.5° C.) consisting of 742 g (60% yield) of 1,1,3-trimethoxy-2-methyl-butane (content according to GC: 96.4%) as a colourless liquid and a 2nd fraction (b.p. 83.5-85° C.) consisting of 87.5 g (6.3% yield) of 1,1,3-trimethoxy-2-butane (content according to GC: 86%), likewise as a colourless liquid, i.e. a total yield of 66.3% of the desired product.