Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:9]([O:11]C)=[O:10])=[CH:6][NH:7][CH:8]=1.I[CH2:14][CH3:15].[OH-].[Na+]>C(O)C.CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:4]([CH3:3])[C:5]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH3:15]
Reactant: COC(=O)c1c[nH]cc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCn1cc(C)c(C(=O)O)c1
Yield: 73.1 %

Procedure:
In the same manner as in Reference Example 37 and using 60% sodium hydride (340 mg, 8.62 mmol), N,N-dimethylformamide (25 mL), methyl 4-methyl-1H-pyrrole-3-carboxylate (1.00 g, 7.19 mmol), iodoethane (860 μL, 10.8 mmol), ethanol (6 mL) and 8N aqueous sodium hydroxide solution (1.8 mL) as starting materials, the title compound (805 mg, 73%) was obtained as a white solid.
Reaction SMILES: C=O.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:27](OCC)(=O)C>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH2:27][N:22]([C:23](=[O:25])[CH3:24])[CH:20]([CH3:21])[CH2:19]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(CC(C)NC(C)=O)cc1OCc1ccccc1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)N(C(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Paraformaldehyde (6.32 g) was added portionwise to a solution of 211 (2.21 g, 7.04 mmol) in toluene (55 ml) with pTSA (60 mg). The reaction mixture was heated under reflux for 2 h. Further paraformaldehyde (632 mg) was added and heating under reflux was continued overnight. Additional pTSA (60 mg) and paraformaldehyde (1.9 g) was added to the reaction mixture portionwise over 2 h. The solution was cooled to rt, water (50 ml) and ethyl acetate (60 ml) were added. The layers were separated and the organic layer was washed with water (2×50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (2.15 g, 94%) as a colourless oil. 1H NMR indicated a mixture of conformers, signals for both conformers are listed 1.04, 1.12 (3H, d, J=6.7 Hz, CH3CH), 2.14, 2.17 (3H, s, CH3CO), 2.38-2.51 (1H, m, CHH for both conformers), 2.89-3.06 (1H, m, CHH for both conformers), 3.84, 3.85 (3H, s, OCH3), 4.06-4.6 (2H, m, CH2 for both conformers), 5.01-5.02 (3H, m, CHCH3 and CH2Ph for both conformers), 6.6-6.64 (2H, m, 2×CH for both conformers), 7.28-7.44 (5H, m, 5×CH, phenyl for both conformers). LC/MS (ES+) tr=1.02 min, m/z 348.19 (M++Na).
Reaction SMILES: C(N(CC1C=CC=CC=1)C1(C[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[NH:47]1[CH2:52][CH2:51][CH2:50][CH:49]([C:53](N)=[O:54])[CH2:48]1>>[O:39]=[S:30]1(=[O:38])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][C:53]([CH:49]3[CH2:50][CH2:51][CH2:52][NH:47][CH2:48]3)=[O:54])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: NC(=O)C1CCCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CCCNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and piperidine-3-carboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.47 (s, 1 H), 8.11 (s, 1 H), 8.07-8.05 (d, J=1.2 Hz, 1 H), 7.98-7.96 (d, J=7.2 Hz, 1 H), 7.83-7.80 (d, J=8.4 Hz, 1 H), 7.70-7.64 (m, 2 H), 7.58-7.54 (m, 1 H), 5.29 (s, 1 H), 4.61 (s, 2 H), 3.76 (s, 2 H), 3.55-3.52 (m, 2 H), 3.43-3.34 (m, 3 H), 3.22-3.15 (m, 1 H), 2.52 (s, 3 H), 2.29-2.27 (m, 1 H), 2.06-2.02 (m, 1 H), 1.97-1.89 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Example 23 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([OH:10])=[N:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>COCCOC>[CH2:14]([O:13][C:11]([C:6]1[N:7]=[C:8]([OH:10])[S:9][C:5]=1[C:3]1[N:16]=[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:12])[CH3:15]
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)c1nc(O)sc1C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1nc(O)sc1-c1cn2cccc(C)c2n1
Yield: 58 %

Procedure:
A solution of ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (2.94 g) and 2-amino-3-methylpyridine (3.24 g) in 1,2-dimethoxyethane (100 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diethyl ether and recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(4-ethoxycarbonyl-2-hydroxy-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (1.76 g). mp 240°-242° C. (dec.).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=O)(=O)[CH3:2].[CH:9]1([NH:15][C:16](=[O:21])[CH2:17]C(C)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH:9]1([NH:15][C:16]([C:17]2[CH:6]=[C:5]([CH3:8])[O:4][C:1]=2[CH3:2])=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)CC(=O)NC1CCCCC1
Reactant: CC(=O)OC(C)C=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)NC2CCCCC2)c(C)o1
Temperature: 25 °C

Procedure:
24 parts (by weight) of α-acetoxypropionaldehyde is stirred with 36.6 parts of acetoacetic cyclohexylamide and 1 part of concentrated H2SO4 in 100 parts of toluene for 3 hours at 50° C. After the mixture has been cooled to room temperature it is washed with sodium hydrogen carbonate. The organic phase is dried with Na2SO4 and concentrated to dryness. There is obtained 41 parts of 2,5-dimethylfuran-3-carboxylic cyclohexylamide having a melting point of 111° to 113° C. After recrystallization from cyclohexane the compound melts at 114° to 115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:8]=3[S:7][C:6]=2[CH:26]=1.[OH:27][CH2:28][CH2:29]CN1CCNCC1.C(Cl)(Cl)Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:29][CH2:28][OH:27])[CH2:16][CH2:17]3)[C:9]3[CH:19]=[C:20]([CH:23]([CH3:24])[CH3:25])[CH:21]=[CH:22][C:8]=3[S:7][C:6]=2[CH:26]=1
Reactant: OCCCN1CCNCC1
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(C)CC1)Cc1ccc(F)cc1S2
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccc(F)cc1S2

Procedure:
A mixture of 4.0 g 10-chloro-3-fluoro-8-isopropyl-10,11-dihydrodibenzo (b,f) thiepin (Example 1), 4.0 g 1-(3-hydroxypropyl) piperazine (T. Zawisa et al., Acta Polon. Pharm. 22, 477, 1965) and 7 ml of chloroform was refluxed for 5 hours and then processed in the manner described in Example 2. 4.4 g (76%) of an oily base which was converted to a crystalline dimaleate, m.p. 106°-108° C. (ethanol) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)C[C:13]2(CC2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[S:57]1CCNC1>>[CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][CH2:13][S:57][CH:17]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][CH2:43][CH2:42][N:41]5[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: C1CSCN1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5SCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
was prepared in a similar fashion to (1-{6-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DW), replacing the cyclopropyl proline carboxylic acid with the corresponding thiazolidine derivative.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)N1CCN=C1[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(CBr)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
2-(tert-Butyl-dimethyl-silyl)-4,5-dihydro-imidazole-1-sulfonic acid dimethylamide (5.03 g) (prepared as described by Ngochindo, J. Chem. Soc. Perkin Trans. (1990) 1:1645) was dissolved in 100 ml of dry tetrahydrofuran and cooled in a dry ice-acetone bath to -78° C.; 11.9 ml of 1.6M n-butyllithium in hexane was added to this mixture. After 1 hr at -78° C., the reaction mixture was treated dropwise with 5.0 g of 4-bromomethyl-1-methyl-2-nitro-benzene dissolved in 25 ml of dry tetrahydrofuran (THF). The mixture was stirred at -78° C. for 1 hr and then allowed to come to room temperature overnight. The mixture was treated with saturated ammonium chloride, extracted with ethyl acetate washed the combined extracts with saturated sodium chloride, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel and eluted with ethyl acetate:hexane (1:4 ) to give 2.39 g of 2-(tert-butyl-dimethyl-silyl)-5-(4-methyl-3-nitro-benzyl)-imidazole-1-sulfonic acid dimethylamide as a yellow oil. ##STR126##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:30]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:29]=1[F:28])=[CH:13][CH:12]=[C:11]([C:24]([F:25])([F:26])[F:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)ccc1F

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 2-fluoro-5-trifluoromethylphenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(2-fluoro-5-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a slight yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=[C:19]2[S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:20]=[C:19]2[S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(N)ccc21
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
2-Methylsulfonyl-N-[3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 0.44 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.61 g of 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 10 ml of pyridine. The reaction mixture is then stirred for 1 hour at a temperature in the region of 0° C. and then 2 hours at a temperature in the region of 20° C. After filtration through sintered glass, the filtrate is diluted with a mixture of 45 ml of ethyl acetate and 30 ml of water. After settling out, the organic phase is washed with 2 times 30 ml of water. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 150 g of silica (particle size 20-40 μm), eluting successively with cyclohexane/ethyl acetate (90/10; 85/15; 70/30 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.68 g of 2-methylsulfonyl-N-[3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide is thus obtained in the form of a burgundy-colored paste (Rf=0.35, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (70/30 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)=[CH:4][C:3]=1[CH3:16].C(OC([N:24]1[CH2:29][CH2:28][NH:27][C:26]([CH3:31])([CH3:30])[CH2:25]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:30][C:26]1([CH3:31])[CH2:25][NH:24][CH2:29][CH2:28][N:27]1[C:13]([C:10]1[N:11]=[CH:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:16])[CH:4]=2)[N:9]=1)=[O:15]
Reactant: Cc1cc(-n2cnc(C(=O)O)n2)ccc1F
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-n2cnc(C(=O)N3CCNCC3(C)C)n2)ccc1F

Procedure:
This intermediate was prepared from 1-(4-fluoro-3-methyl-phenyl)-1H-[1,2,4]triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:37])[N:24]([CH:34]([CH3:36])[CH3:35])[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:20]=[C:19]([Cl:38])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:34]([CH3:36])[CH3:35])[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:37]
Reactant: CC(C)N(CCOc1ccccn1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCOc1ccccn1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Yield: 18.5 %

Procedure:
A solution of {2-[3-chloro-5-(isopropyl-2-(pyridin-2-yloxy)-ethyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.033 g) and TFA (0.4 ml) in dichloromethane (0.4 ml) was stirred at room temp for 3 h then concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with dichloromethane/methanol/ammonia (94:6:1) to give the title compound as a colourless gum (0.005 g).
Reaction SMILES: [Na].Cl.[CH:3]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4]1.C([O:11][C:12](=O)[CH:13]([F:19])[C:14](OCC)=[O:15])C.Cl>CO.O>[CH:3]1([C:6]2[N:7]=[C:14]([OH:15])[C:13]([F:19])=[C:12]([OH:11])[N:8]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: Oc1nc(C2CC2)nc(O)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60° C. for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro-4,6-pyrimidinediol 3 (3.6 g, 76%) is obtained as a white powder and used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40].C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:45]5[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 60 °C
Yield: 34.5 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added 1-methane sulfonyl piperazine (181 mg, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (85 mg, 35%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.55-7.20 (m, 5H), 6.50 (s, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.15 (m, 4H), 2.55 (m, 6H), 2.00 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 670 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:36][CH2:37][CH3:38])=[C:28]([CH:35]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:36][CH2:37][CH3:38])=[C:28]([CH:35]=2)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:4][CH:5]=1
Reactant: CCCc1ccc(O)cc1OCC(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.79 g), methyl 2-(5-hydroxy-2-propylphenoxy)acetate (1.17 g), anhydrous potassium carbonate (0.72 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.60 g, 61%) of methyl 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])O[C:3]1([O:13]C)[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][C:2]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:13]
Reactant: C1COCCN1
Reactant: COC1(c2ccc(SC)cc2)OC1(C)C
Product: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1

Procedure:
151.4 g (0.675 mol) of 3,3-dimethyl-2-methoxy-2-[4-(methylthio)-phenyl]-oxirane (melting point 62°-64° C.) are dissolved in 235.2 g (2.70 mols) of morpholine and the solution is warmed to reflux temperature.