Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:22]1([CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:6][CH2:5]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 13 parts of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one, 12.4 parts of 1,1'-(bromomethylene)bis[benzene], 6.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling to room temperature, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11]3=[C:27]([CH3:31])[N:28]=[C:29]([CH3:30])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[CH3:31][C:27]1[N:28]=[C:29]([CH3:30])[N:10]2[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)=[N:13][C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=1)=[N:9]2
Reactant: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(-c3cccc(NS(C)(=O)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
A solution of 80 mg (0.19 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)-imidazo[5,1-f][1,2,4]triazin-2-yl]aniline from example 7, 20 mg (0.19 mmol) of methanesulfonyl chloride and 40 mg (0.38 mmol) of triethylamine in dichloromethane is stirred overnight at 20° C. The mixture is washed with aqueous sodium hydrogencarbonate solution, and the organic phase is dried and purified by HPLC.
Reaction SMILES: C(OC([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:11])C)(=O)C(C)C.C(=O)([O-])OC1C=C[CH:28]=[C:27]([CH:31]([O:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])C)[C:26]=1[N+]([O-])=O>>[C:34]([O:33][CH:31]([O:11][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH:27]([CH3:26])[CH3:28])(=[O:38])[CH:35]([CH3:36])[CH3:37]
Reactant: CC(C)C(=O)OC(C)c1cccc(OC(=O)[O-])c1[N+](=O)[O-]
Reactant: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Product: CC(C)CC(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CC(=O)O
Yield: 51 %

Procedure:
Following the procedure of preparation for (110), and substituting (114) for (111), provided the title compound as a mixture of two diastereomers in 51% yield. 1H-NMR (CDCl3, 400 MHz): δ 0.89 (m, 12H), 1.17 (m, 8H), 1.65 (m, 1H), 2.02 (m, 1H), 2.16 (m, 1H), 2.33 (m, 2H), 2.56 (m, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 5.00 (m, 1H), 6.57-6.56 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C:10]([CH2:19][OH:20])([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.CC1CCCO1.C1(C)C(S(O)(=O)=O)=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:9][C@@:10]([CH2:19][OH:20])([CH2:17][O:18]2)[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@H:13]3[OH:14])=[CH:4][C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC1CCCO1
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of (2S,3R,4S,5S)-2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-6,6-bis-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (580 mg, 1.32 mmol) in a mixture of dichloromethane (5 mL) of and 2-methyl-tetrahydrofuran (5 mL) was added Silicycle® Si-Tosic acid derivatized silica gel (40-63 micrometer, 0.68 mmol/g) Silicagel bound toluenesulfonic acid (1 g) and the reaction mixture was allowed to stir at room temperature overnight (˜16 hours). The mixture was filtered through a plug of Celite® and the plug rinsed with dichloromethane:2-methyl-tetrahydrofuran (40 mL; 1:1 volume). The crude material was purified by preparative HPLC on a Phenomenex Gemini NX 150×21.2 5 mm column eluting with a flow rate of 28 mL/minute; mobile phases A: water with 1% ammonium hydroxide modifier and B: methanol with 1% ammonium hydroxide modifier. The product was eluted using a gradient of 5% methanol with 1% ammonium hydroxide modifier for 1.5 minutes and increased in a linear gradient to 100% methanol with 1% ammonium hydroxide modifier over 8.5 minutes to give the product (375 mg; 69.7% yield, retention time=9.8 minute). LCMS 407 (M−H+, negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.56 (d, J=7.8 Hz, 1 H), 3.61 (d, J=7.3 Hz, 1 H), 3.66 (t, J=8.2 Hz, 1 H), 3.69 (d, J=12.4 Hz, 1 H), 3.79 (d, J=8.3 Hz, 1 H), 3.85 (d, J=12.4 Hz, 1 H), 4.01 (s, 2 H), 4.16 (d, J=7.3 Hz, 1 H), 6.69 (d, J=8.3 Hz, 2 H), 7.02 (d, J=8.3 Hz, 2 H), 7.34-7.37 (m, 1 H), 7.37-7.41 (m, 1 H), 7.45 (d, J=1.5 Hz, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: BrCc1cccs1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(OCc2cccs2)cc1

Procedure:
To a solution of 51.75 g (0.29 m) of 2-bromomethylthiophene and 38.6 g (0.3 m) of 4-chlorophenol in 400 ml of acetonitrile was added, all at once, 38.6 g of powdered potassium carbonate. The resulting mixture was stirred and heated at reflux for one (1) hour. The solvent was removed by evaporation under reduced pressure and 400 ml of water was added to the residue. The resulting aqueous mixture was extracted three times with 200 ml portions of ether. The organic extracts were combined and then washed sequentially with 50 ml of a 10 percent sodium hydroxide solution, 300 ml of water and 300 ml of a saturated sodium chloride solution. The extracts were dried over magnesium sulfate and the solvent removed by evaporation under reduced pressure. The residue was an orange oil which slowly solidified upon standing. Distillation of the residue gave a main fraction boiling at 96°-100° C. at 0.01 millimeter of mercury. The crude product slowly crystallized and was purified by recrystallization from hexane. The (4-chlorophenoxy)methylthiopene product, a white solid, was recovered in a yield of 41 g (63 percent of theoretical) and melted at 45°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:28]=[O:29])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[N:16]([C:17]=2[CH:28]=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc3ccccn3c2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ccccn3c2C=O)cc1
Temperature: 55 °C
Reaction time: 0.67 h

Procedure:
A slurry of 20 g of 2-(4-methoxy phenyl) indolizine in 35 ml of DMF was added to a solution of 10 ml of phosphorus oxychloride in 30 ml of DMF at 10°-20° C. After the reaction solution was stirred at 40° for 40 min., it was added to 200 g of ice. 120 g of 25 percent sodium hydroxide solution was added and the resulting mixture was heated to 55° C., cooled, and filtered. The air-dried product weighed 23 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: COCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was added and the reaction mixture was stirred for an additional 15 minutes. Morpholine (581 mg, 6.60 mmol) was added in one portion. After stirring for 18 hours the solution was concentrated under reduced pressure. The resulting foam was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous washes were extracted with chloroform. The combined organic fractions were concentrated under reduced pressure and then purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-20% CMA over 1500 mL, followed by 20-25% CMA over 500 mL, and finally 25-30% CMA over 500 mL). A final recrystallization from acetonitrile provided 913 mg of 3-[4-amino-2-(methoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 215-217° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][Si](O[Si](C)(C)C)(C)C.IC>CN(C)C=O>[N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: O=c1[nH]cc([N+](=O)[O-])c(=O)[nH]1
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-nitrouracil (10.00g, 64 mmole), 1,1,1-3,3,3-hexamethyldisilazane (40 mL, 190 mmole) and chlorotrimethylsilane(4.0 mL, 0.32 mmole) are heated to reflux for 24 hours. The solution is concentrated under reduced pressure to afford 5-nitrouracil bis (trimethylsilyl) ether. 5-nitrouracil bis(trimethylsilyl)ether (10.0 g, 24 mmole), dimethylformamide (50 mL) and iodomethane (3.0 mL, 49 mmole) are heated in an 80° C. oil bath for 24 hours. Ice water is added, and the mixture is stirred for 30 minutes, then extracted with dichloromethane (3×). The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[F:10][C:5]1[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:7][C:6]=1[CH2:8][OH:9]
Reactant: OCc1cc(Br)ccc1F
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: OCc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound {2-fluoro-5-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-phenyl}-methanol (MS m/e: 315.1 [M+H]+) was prepared from (5-bromo-2-fluoro-phenyl)-methanol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:7]1C[C:9](=O)[CH2:10]2)=[O:5])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH:7]2[CH2:9][CH2:10][CH:11]1[CH2:12][C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:14]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCCC1CC(=O)C2
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCOC(=O)N1C2C=C(N3CCCC3)CC1CC2
Reaction time: 110 h
Yield: 98.7 %

Procedure:
36.6 g of 8-azabicyclo[3,2,1]octan-3-one-8-carboxylic acid ethyl ester (e) are dissolved in 500 ml of absolute petroleum ether, and 52.8 g of pyrrolidine are added. A solution of 19.4 g of titanium tetrachloride in 100 ml of petroleum ether is added dropwise within 70 minutes, with vigorous stirring. With slight warming of the solution, a light-yellow precipitate is immediately precipitated. After 110 hours' stirring at roomtemperature, the precipitate is allowed to settle and the yellow petroleum ether solution is decanted. The precipitate is suspended in 250 ml of anhydrous benzene, suction filtered, and washed with benzene. The united organic phases are concentrated in a vacuum; the oil which remains behind is purified by vacuum distillation to obtain 42.8 g (92.2 percent) of (d) as a light-yellow, viscous oil (b.p. 125° to 128° C. at 8 Pa.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>C1COCC1.CCOC(C)=O>[OH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NCCOCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCCOCCO)c3)n2)n1
Yield: 61.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with commercially available 2-(2-aminoethoxy)ethanol (0.194 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.210 g, 61%) as a white solid. MS (ISP) 558.2 [(M+H)+]; mp 123° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[S:15])[NH:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[C:17](OCC)(=[O:23])[C:18](OCC)=[O:19].Cl>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:18](=[O:19])[C:17](=[O:23])[NH:14][NH:13][C:12]1=[S:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(=S)NN
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1c(=S)[nH][nH]c(=O)c1=O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
4-(2-tert.-Butoxycarbonylamino-ethyl)-thiosemicarbazide (9.37 g) is added to a solution of sodium (0.92 g) in methanol (40 cc) at 20° C., and diethyl oxalate (5.4 g) is then introduced dropwise in the course of 10 minutes. The mixture is heated under reflux for 3 hours. It is allowed to cool, water (100 cc) is added, concentrated hydrochloric acid (3 cc) is introduced dropwise, the mixture is extracted with ethyl acetate (2×100 cc) and the extract is washed with a saturated sodium chloride solution (2×50 cc), dried over sodium sulphate, filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is taken up in methylene chloride (65 cc), the crystallisation is started, the batch is left for 2 hours at 20° C. and then filtered, and white crystals (4.59 g) of 4-(2-tert.-butoxycarbonylamino-ethyl)-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine, melting at 160° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[S:27][C:26]([CH2:28]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:26]3[S:27][C:23]([Br:22])=[CH:24][CH:25]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: ClCc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCc3ccc(Br)s3)cc2)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
3.5 g of 4-(6-chloro-2-pyridinyloxy)-phenol and 3.2 g of potassium carbonate are stirred for one hour at 60° C. in 100 ml of anhydrous dimethylformamide. Subsequently, 6.5 g of 5-bromo-2-chloromethylthiophene in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 6 hours at 80° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 200 ml of ice water. The crude product which precipitates out is filtered off and recrystallized from n-hexane/ethyl acetate (4/1). There is obtained 3.1 g of 2-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-5-bromothiophene of m.p.: 78°-80° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@H:23]3[C:24]([OH:26])=[O:25])=[O:21])=[CH:11][CH:10]=2)=[C:4]([CH:33]=O)[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:41][OH:42].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@H:23]3[C:24]([OH:26])=[O:25])=[O:21])=[CH:11][CH:10]=2)=[C:4]([CH:33]=[N:41][OH:42])[CH:3]=1
Reactant: O=Cc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)N3CCC[C@H]3C(=O)O)c2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3C=NO)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
The compound (20 mg, 0.043 mmol) of Example 43 was dissolved in acetic acid (5 mL), and sodium acetate (45 mg, 0.56 mmol) and hydroxylamine hydrochloride (14 mg, 0.21 mmol) were added thereto, and stirred at 60° C. for 2 hours. After that, acetic anhydride (0.026 mL, 0.28 mmol) was added thereto, and stirred at 100° C. for 2 hours. After cooling, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[C:31]#[C:32][CH:33]([OH:36])[CH2:34][CH3:35])[CH2:11][CH2:10]1)(=[O:8])=[O:7].[H-].[Na+].[CH3:39]I>C1COCC1>[F:28][C:26]([F:27])([F:29])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[CH2:10][CH2:11]2)=[C:16]([C:31]#[C:32][CH:33]([O:36][CH3:39])[CH2:34][CH3:35])[CH:17]=1)([OH:30])[C:22]([F:25])([F:23])[F:24]
Reactant: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
To a solution of 1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol (186 mg, 0.33 mmol, Example 154) in dry THF (5 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil, 134 mg, 3.34 mmol). The reaction mixture was stirred at room temperature for 10 min then methyl iodide (0.21 mL, 3.34 mmol) was added. After stirring for an additional 2 h, the solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 10 to 30% ethyl acetate in hexanes), to provide 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxy-1-pentyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (156 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([CH2:13][Br:14])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(F)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(F)c1CBr
Yield: 82.5 %

Procedure:
To a solution of 11 g of ethyl 3-fluoro-2-methylbenzoate in 300 ml of carbon tetrachloride is added 12 g of N-bromosuccinimide and the mixture is refluxed with heating for 12 hours. After cooling, the mixture is washed with water and a saturated saline solution and dried over magnesium sulfate and the solvent is distilled off under reduced pressure to give 13 g of ethyl 3-fluoro-2-bromomethylbenzoate. Mass spectrum m/z: 262, 260(M+).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1>Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[NH:18][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([N:5]=[C:1]=[S:2])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N=C=S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After repetition of the previous steps, thiophosgene (0.5 ml) was added dropwise to a stirred solution of 6-amino4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline (1.65 g) in 2N aqueous hydrochloric acid (45 ml). The mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated and dried to give 4-(3-chloro-4-fluoroanilino)-6-isothiocyanato-7-methoxyquinazoline which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13](N)=[O:14])[CH:12]=1)[CH3:2].[OH-:25].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([OH:14])=[O:25])[CH:12]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1ccccc1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Agent: [Na+]
Solvent: CCO
Product: CCc1ccccc1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Yield: 99.8 %

Procedure:
8-(2-ethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (1.0 g, 0.0031 mol) and sodium hydroxide (1.2 g, 0.031 mol) were solved in ethanol (95%)(30 ml) and was refluxed overnight. The solvent was evaporated under reduced pressure and to the residue was added water. The pH was adjusted to 7 by addition of conc HCl (2.6 ml) and the solid that precipitated was isolated by filtration, washed with water and dried to give 1.0 g (99%) of the title compound.