Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:37]=[CH:36][CH:35]=[CH:34][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([O:26]C)=[O:25])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:9].[OH-].[K+]>C(O)(C)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:37]=[CH:36][CH:35]=[CH:34][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]([OH:26])=[O:25])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)=[O:9]
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccco3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1ccc(N2CCN(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
A mixture of intermediate (30) (0.0006 mol) and potassium hydroxide (0.006 mol) in isopropanol (5 ml) was stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in isopropanol/HCl 6N and converted into the hydrochloric acid salt. The precipitate was filtered off and dried, yielding 0.31 g of 4-[4-[[2-(2-furanyl)benzoyl]amino]phenyl]-α-phenyl-1-piperazineacetic acid (intermediate 31).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@:19]3(O)[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:24])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].O>C(O)(=O)C>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH:18]=3)([CH3:16])[C:14](=[O:24])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@]21O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 30 %

Procedure:
3-Acetoxy-9α-hydroxyoestra-1,3,5(10)-trien-17-one (100 mg) was reacted with ceric ammonium nitrate (0.33 g) in 90% aqueous acetic acid (50 ml) for 1 hour. The mixture was poured into water and extracted with ether to yield title compound (30%) m.p. 188°-190° and also 3-acetoxyoestra-1,3,5(10),9(11)-tetraen-17-one (30%) arising from acid dehydration of the 9α-hydroxy starting material and indicating that the starting material for the ceric oxidation is in fact the Δ9(11) compound formed in situ.
Reaction SMILES: Br[CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:19][CH3:20])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:19][CH3:20])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1c2cc(C)c3[nH]c(=O)c(C)cc3c2OC1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1c2cc(C)c3[nH]c(=O)c(C)cc3c2OC1CN=[N+]=[N-]
Yield: 57.5 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 274 using the compound obtained in Example 292 (46 mg, 0.14 mmol), sodium azide (53 mg, 0.82 mmol) and dimethylformamide (1.0 ml). 24 mg of the title compound was obtained as a pale yellow solid (58.8%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])[CH2:9][CH2:10][CH3:11])(C)(C)C.Cl>O1CCOCC1>[ClH:24].[NH2:7][C@@H:8]([CH2:9][CH2:10][CH3:11])[CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15]
Reactant: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC[C@H](N)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ((S)-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-carbamic acid tert-butyl ester (1.30 g, 3.49 mmol) in 1,4-dioxane (20 mL) is added HCl (50 mL of a 4 M solution in 1,4-dioxane, 200 mmol) and the reaction mixture is stirred at RT for 16 h. The reaction mixture is concentrated in vacuo and the yellow solid obtained is triturated with diethyl ether; the diethyl ether layer is decanted and the product is dissolved in a minimal volume of MeOH and is precipitated by the addition of diethyl ether. The solvent is decanted and the resulting solid is dried under vacuum to afford the title compound.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:8]([NH:10][C@H:11]([C:18](OC)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].O.[NH2:30][NH2:31]>CO>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:30][NH2:31])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
27.9 g of Boc-Gln-His-OCH3 (Marchiori et al., J. Chem. Soc (C) 1967, 81) are dissolved in 280 ml of highest purity methanol, 28 ml of hydrazine hydrate are added and the mixture is left to stand for 20 hours at 25°C. It is concentrated to dryness in a high vacuum and the residue is recrystallised from methanol-ethyl acetate-petroleum ether. Melting point 187°-189°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.O=O>CO.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Clc1cc(Br)cc2c1NCC2
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: CO
Product: Clc1cc(Br)cc2cc[nH]c12
Yield: 88.3 %

Procedure:
A mixture of Example 65B (0.120 g, 0.55 mmol) and salcomine (0.022 g, 0.06 mmol) in methanol (30 mL) was treated with oxygen over 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel to provide 0.112 g of the desired product. MS (ESI(+)) m/z 232 (M+2) and 248 (M+NH4)+;
Reaction SMILES: C(S[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C)[CH:13]=2)[NH:8][C:7]=1[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].CCS.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl>[OH:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:6]2
Reactant: COC(=O)C(C)(C)Cc1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of the compound from step A (25.50 g, 73 mmol) in CH2Cl2 (250 ml) at 0° C. was added AlCl3 (87.70 g, 9 mol eq.) portion-wise. When the addition was complete, the ice-bath was removed and the mixture was stirred at RT for 3 hours. EtSH (27 ml, 5 mol eq.) was added and the resulting mixture was stirred for a further 5 hours. It was then slowly poured onto an ice-cold 1M solution of Na, K tartrate. The product was extracted into CH2Cl2 (×2) and the organic phase was washed with aq. NaCl (×3). Conventional work-up followed chromatography on silica gel using EtOAc/hexane 1:5 to 3:2 afforded 13.60 g of the title compound, 75% yield.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:23]=[C:22]([F:32])[CH:21]=2)=[CH:14][C:13]=1[NH:34][C:35](=[O:50])[C:36]1[CH:41]=[C:40]([N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:49].C(O)(=O)C>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[C:20]2[CH:25]=[C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:23]=[C:22]([F:32])[CH:21]=2)=[CH:14][C:13]=1[N:34]1[C:35](=[O:50])[C:36]2[C:37](=[CH:38][CH:39]=[C:40]([N:42]3[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]3)[CH:41]=2)[N:49]=[CH:1]1
Reactant: CCOC(OCC)OCC
Reactant: CN1CCN(c2ccc(N)c(C(=O)Nc3cc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)ccc3F)c2)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(c2ccc3ncn(-c4cc(NC(=O)c5cc(F)cc(N6CCOCC6)c5)ccc4F)c(=O)c3c2)CC1

Procedure:
Triethyl orthoformate (0.123 ml) was added to a stirred mixture of N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide (0.31 g), glacial acetic acid (0.016 ml) and ethanol (4 ml) and the resultant mixture was heated to 76° C. for 18 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic solution was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.119 g); NMR Spectrum: (DMSOd6) 2.23 (s, 3H), 3.22 (m, 4H), 3.72 (m, 4H), 6.99 (d, 1H), 7.12 (d, 1H), 7.29 (s, 1H), 7.47 (m, 2H), 7.63 (s, 1H), 7.89 (m, 1H), 7.97 (m, 1H), 8.18 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H+ 561.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]([CH3:28])[CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:52](OC2C=CC=CC=2)=[N:53][C:54]#[N:55])=CC=1>O1CCCC1.C(O)(C)C.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]([CH3:28])[CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)/[C:52](=[N:53]/[C:54]#[N:55])/[NH:29][C:15]=2[CH:14]=1
Reactant: C[C@H](CN1CCOCC1)Nc1ccc(/C=C2\c3ccc(F)cc3COc3cc(F)ccc32)cc1[N+](=O)[O-]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pt]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](CN1CCOCC1)n1/c(=N/C#N)[nH]c2cc(/C=C3\c4ccc(F)cc4COc4cc(F)ccc43)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.9 %

Procedure:
Dissolve (R)-[4-((E)-3,8-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(1-methyl-2-morpholin-4-yl-ethyl)-amine (0.017 mol, 9.0 g) in tetrahydrofuran (35 mL) and isopropanol (90 mL). Add triethylamine (0.039 mol, 3.9) and 10% platinum on carbon (1.5 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 2 h. Filter off the catalyst through a plug of diatomaceous earth. Dilute the filtrate with dioxane (35 mL), add diphenyl N-cyanocarbonimidate (0.019 mol, 4.61 g) and stir at room temperature for 48 h. Concentrate the reaction mixture under reduced pressure. Purify on a silica gel column using 0.5% methanol in dichloromethane as eluent to obtain the title compound (6.0 g, 64%) as an off-white solid. LC-MS m/z 528.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5](F)=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].[NH2:24][NH2:25]>CN(C=O)C>[CH3:12][O:11][C:9]([C:8]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:6]([F:22])[C:5]2[C:4](=[C:1]([CH3:2])[NH:24][N:25]=2)[CH:13]=1)=[O:10]
Reactant: NN
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)[nH]nc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 150.5 %

Procedure:
To a solution of methyl 5-acetyl-2-(2-fluorophenylamino)-3,4-difluorobenzoate (500 mg, 1.55 mmol, from step D in example 3) in DMF (10 ml) was added hydrazine (0.06 mL, 1.85 mmol). After stirring at room temperature for 16 h, the reaction was quenched with NH4Cl solution and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 740 mg (75%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7](C)=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Cl[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1cc(COc2ccc(-c3ccccc3)cc2)co1

Procedure:
Compound (77) was prepared from compound (20) and (4-chloro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.93 mins, m/z (ES−)=341 and 343 (M−H for C19H15ClO4).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][NH:39]3)O1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:14]=[N:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[N:38]1
Reactant: CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CNC(=O)c1cncc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with methylamine hydrochloride via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide (41 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 10.6 mg of 344. MS (Q1) 472.0 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22](O)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:27])[CH3:26])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(O)CO[Si](C)(C)C(C)(C)C)nc3N21
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CCO[Si](C)(C)C(C)(C)C)nc3N21
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 0.70 g (4R,9aR)-6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-ethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 10 ml dichloromethane was added at room temperature 0.794 g tetrabromo methane and 0.628 g triphenylphosphine and the mixture was stirred at this temperature for 30 min. The reaction mixture was purified by chromatography on silica gel with heptane:ethyl acetate=2:1. The product (0.66 g) was taken up in 10 ml tetrahydrofuran. To the resulting solution was added a solution of 0.218 g potassium fluoride in 2 ml water, 0.028 g palladium acetate and 0.50 ml polymethylhydroxysilane and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated, the organic phase was washed with water and brine dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.329 g (4R,9aR)-6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as slightly yellow oil (MS: 448.5 (M+H+))
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl>CCO>[ClH:8].[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=2)[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 70.1 %

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (10.0 g, 61.0 mmol, 1.0 eq), 4-trifluoromethylaniline (8.34 mL, 67.1 mmol, 1.1 eq), EtOH (80 mL), and concentrated HCl (2.5 mL, 30.5 mmol, 0.5 eq) was heated to 80° C. for 24 h and then cooled to rt. The resulting precipitate was collected by filtration, rinsed with EtOH, and dried under vacuum at 50° C. for 18 h to provide the title compound as a white solid (13.9 g, 70%). MS (ESI): mass calcd. for C11H9ClF3N4 [M+H]+, 289.0; m/z found, 289.0. 1H NMR (d6-DMSO): 9.26 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 7.94 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 6.41 (br s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:37])[C:23]3[C:24](=[C:26]([CH2:35][CH3:36])[N:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:38]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[CH:16][N:15]=1)[CH3:12].[CH3:49][O:50]CCO>>[CH2:35]([C:26]1[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:28]=[C:23]2[C:22](=[O:37])[NH:21][C:20]([C:19]3[C:14]([O:13][CH2:11][CH2:12][O:50][CH3:49])=[N:15][CH:16]=[C:17]([S:38]([N:41]4[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]4)(=[O:40])=[O:39])[CH:18]=3)=[N:25][C:24]=12)[CH3:36]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccccc3)nc2c(=O)[nH]1
Reactant: COCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCOC)[nH]c(=O)c2nn1-c1ccccc1

Procedure:
Potassium bis(trimethylsilyl)amide (294 mg, 1.47 mmol) was added to a solution of the compound from example 66 (200 mg, 0.37 mmol) in 2-methoxyethanol (10 ml), and the reaction heated under reflux for 18 hours. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.5) as eluant. The product was recrystallised from dichloromethane:iso-propanol to give the desired compound as a white solid, 82 mg.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:26]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Phenol (47 g; 0.5 mol) is dissolved in DMF (300 ml), and K2CO3 (82.93 g; 0.6 mol) is added. 1-Bromododecane (124.6 g; 0.5 mol) is then added dropwise to the solution at 70° C. After a further 15 hours at 80° C., cooling to 25° C. is carried out, followed by dilution with water (500 ml) and extraction with tert-butyl methyl ether (2×250 ml). The combined organic extracts are washed with water (2×250 ml) and dried over Na2SO4. After filtration, concentration to dryness by evaporation is carried out.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[CH2:22]=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][OH:23])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: C=O
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-chloro-2'-fluoro-2-(imidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 5-chloro-2'-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
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]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].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[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][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]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)ncnc2cc1OCCCl
Reactant: C1CCNC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCCC1
Yield: 17.1 %

Procedure:
To the intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (225 mg, 0.426 mmol) from Example 79A was added pyrrolidine (0.105 mL, 1.278 mmol) in the manner described in Example 80 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (41 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50 (s, 1H), 4.30 (m, 2H), 4.00-3.75 (m, 7H), 2.55 (m, 2H), 1.98 (m, 4H), 1.30 (s, 9H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[N+:12]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])([O-])=[O:13].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH:2]([C:3]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:12][O:13][C:4]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:11])[CH3:1]
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: CC(C)C#Cc1ccccn1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1noc(-c2ccccn2)c1C(C)C
Yield: 2.8 %

Procedure:
A solution of (3-methylbut-1-ynyl)pyridine (170 mg, 1.17 mmol), dimethyl nitromalonate (0.395 mL, 2.93 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.024 mL, 0.117 mmol) in toluene (7 mL) was heated to 170° C. for 120 minutes under microwave. The reaction mixture was concentrated and purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-isopropyl-5-(pyridin-2-yl)isoxazole-3-carboxylate (11 mg, 0.033 mmol, 2.8% yield). The compound had an HPLC retention time=2.96 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=247.15. 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 3H), 1.38 (s, 3H), 4.02 (s, 3H), 4.03-4.10 (m, 1H), 7.33-7.38 (m, 1H), 7.80-7.90 (m, 2H), and 8.72-8.76 (m, 1H).
Reaction SMILES: O=P(Cl)(Cl)Cl.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.N1C=NC=N1>N1C=CC=CC=1>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:8][CH:9]=1
Reactant: Oc1ncnc2ccccc12
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2ncncc2c1

Procedure:
Intermediates of formula (3) wherein L is 1,2,4-triazol-1-yl, can be prepared, for example, by adding POCl3 dropwise to a mixture of a 4-hydroxyquinazoline (1 equiv.) of formula (9) and 1,2,4-triazole (3 equiv.) in pyridine at room temperature.