Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-chlorobenzeneboronic acid: MS (ESI) m/z 327 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.24 (8H, m), 3.89 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.31 (3H, s), 2.28 (3H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)#[N:12].[OH-].[Na+]>CCOCC>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([CH2:11][NH2:12])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: NCc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
To an ice cold suspension of aluminium chloride (126 mg) in ether (1.5 ml) was added a suspension of lithium aluminium hydride (55 mg) in ether (1.5 ml), followed by stirring for 5 min. A solution of 5-cyanoindole (103 mg) in ether (5 ml) was added dropwise thereto. The mixture was stirred at room temperature for 6 hours, followed by adding aqueous Rochel solution thereto and then stirring for 5 hours. The resulting mixture was basified with 1M aqueous sodium hydroxide solution, extracted twice with ethyl acetate (50 ml), washed with saturated aqueous sodium chlroride solution, dried over magnesium sulfate and then filtered to yield (1H-indol-5-yl)methylamine (93 mg, 88%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1C
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
3-Acetamido-4-methylbenzoic acid (205 g, 1061 mmol) was added portionwise over 45 min to stirred fuming nitric acid (1 L) at −5° C., maintaining a reaction temperature below 0° C. The mixture was stirred for an additional 1 h and then crushed ice (2.5 kg) was added. The mixture was stirred for a further 30 min. The precipite that formed was filtered off and thoroughly washed with water. The resulting cake was air dried and suspended in 1 L of acetic acid at 65° C. The suspension was stirred for 1 hour, allowed to cool down to RT and then filtered. The filtrate was washed with acetic acid and ether to give 3-acetamido-4-methyl-2-nitrobenzoic acid (160 g, 63%) as a white solid. MS (M+H)+ 239.
Reaction SMILES: Br[C:2]1[S:24][C:5]2[N:6]([CH2:22][CH3:23])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[S:24][C:5]=3[N:6]([CH2:22][CH3:23])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CCCO
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)sc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)sc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a suspension of 2-bromo-N-(4-chlorobenzyl)-7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 11) (0.500 g) in diethylamine (12 mL) is added copper iodide (0.067 g) and Pd(PPh3)2Cl2 (0.041 g) followed by addition of 3-butyn-1-ol (0.11 mL). The reaction is stirred at rt for 3 d. The diethylamine is removed in vacuo and the resulting residue is partitioned between H2O (50 mL) and CH2Cl2 (50 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organic layers are washed with a saturated NH4Cl solution (50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo. The resulting yellow solid is recrystallized from methanol to yield 0.312 g (64%) of the title compound as a pale yellow, crystalline solid.
Reaction SMILES: NC1C=CC(C(NC2CCN(C)C2)=O)=CC=1OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[N+:37]([O-])=O)[C:24]([NH:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:25]>>[NH2:37][C:36]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:25])=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: COc1cc(C(=O)NCCN2CCCC2)ccc1[N+](=O)[O-]
Agent: COc1cc(C(=O)NC2CCN(C)C2)ccc1N
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1N

Procedure:
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising 3-methoxy-4-nitro-N-(2-pyrrolidin-1-ylethyl)benzamide (Intermediate 193).
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[NH:19][C:18](=[O:20])[N:17]([C@H:21]([C:30]3[NH:31][C:32]([C:35]4[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][C:36]=4[F:43])=[CH:33][N:34]=3)[C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:16]2=[O:44])=[CH:11][CH:10]=1)(C)(C)C.ClCCl.C(#N)C.[I-].[Na+].Cl[Si](C)(C)C>C(OCC)(=O)C>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:32]2[NH:31][C:30]([C@@H:21]([N:17]3[C:16](=[O:44])[C@@H:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][OH:5])=[CH:14][CH:13]=4)[NH:19][C:18]3=[O:20])[C@H:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:23])=[N:34][CH:33]=2)=[C:36]([F:43])[CH:37]=1)#[CH:42]
Reactant: C#Cc1ccc(-c2cnc([C@H]([C@@H](C)c3ccccc3)N3C(=O)N[C@H](c4ccc(OCCOC(C)(C)C)cc4)C3=O)[nH]2)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C#Cc1ccc(-c2cnc([C@H]([C@@H](C)c3ccccc3)N3C(=O)N[C@H](c4ccc(OCCO)cc4)C3=O)[nH]2)c(F)c1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of (R)-5-[4-(2-tert-butoxy-ethoxy)-phenyl]-3-{(1S,2S)-1-[5-(4-ethynyl-2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-imidazolidine-2,4-dione (293 mg, 0.49 mmol) in 1:1 v/v dichloromethane/acetonitrile (10 mL) at 0° C. under an atmosphere of nitrogen was added sodium iodide (148 mg, 0.99 mmol) followed by chlorotrimethylsilane (184 μL, 1.45 mmol) and the resulting mixture was allowed to stir for 30 minutes. Additional sodium iodide (148 mg, 0.99 mmol) followed by chlorotrimethylsilane (184 μL, 1.45 mmol) was added and stirring continued for 45 minutes. The reaction was then poured into ethyl acetate (30 mL) and washed with 10% w/v aqueous sodium thiosulfate solution. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted with 80 to 100% v/v ethyl acetate in hexanes to give (R)-3-{(1S,2S)-1-[5-(4-ethynyl-2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-5-[4-(2-hydroxy-ethoxy)-phenyl]-imidazolidine-2,4-dione (59 mg, 22%). HR-MS: calcd for C31H27FN4O4 [M+H+] 539.2089. Found 539.2086.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]3[CH:9]=[N:10][NH:11][C:3]=23)=[CH:14][CH:15]=1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: Nc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cc(Nc2ccc(O)cc2)c2[nH]ncc2n1
Yield: 54.5 %

Procedure:
7-Chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (0.5 g, 3 mmol) and 4-aminophenol (0.65 g, 6 mmol) in dry xylene (5 ml) were heated under reflux under nitrogen for 7 h. The resulting solid was collected and washed with water and ethyl acetate, then crystallised from methanol/ethyl acetate to give the hydrochloride salt of the required product (393 mg, 47%), m.p. 308°-310° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[C:6]=1[CH:16]=[CH2:17])=[O:4].BrBr.NC(N)=[S:22].[OH-].[NH4+]>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[S:22][CH:17]=[CH:16][C:6]=12)=[O:4]
Reactant: NC(N)=S
Reactant: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)c1c2ccccc2nc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.8 g (7.2 mmol) Methyl-2-oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylate 5 in 40 mL chloroform was added slowly over a dropping funnel a solution of 1.15 g (7.2 mmol) bromine in 40 mL chloroform and the reaction mixture was stirred for 1 hour at ambient temperature. After evaporation of the solvent the residue was mixed with 40 mL ethanol and 1.7 g (18 mmol) thiourea and refluxed for 2.5 h. After cooling the mixture was poured on ice, the pH-value was adjusted with ammonium hydroxide at pH=7-8 and the solution was extracted with 100 mL chloroform. The organic layer was separated, dried over sodium sulfate and filtered. Then the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with methylene chloride/acetone 9:1, to give 1.0 of the desired product 14.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51](Br)[S:52][CH:53]=1)[CH3:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[S:52][CH:53]=1)[CH3:45]
Reactant: CCOC(=O)Cc1csc(Br)n1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
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: O
Product: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)n1
Temperature: 100 °C
Reaction time: 11 h
Yield: 59.9 %

Procedure:
Degassed N,N-dimethylformamide (0.2 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 15.5 mg, 0.0249 mmol), (2-bromo-thiazol-4-yl)-acetic acid ethyl ester (Example 42; 6.4 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium (0) (4.7 mg, 0.0041 mmol) and potassium phosphate (9 mg, 0.04 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for 11 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/dichloromethane=1/4) to give the title compound (9.7 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (20.0 g, 102 mmol) in DMF (400 ml) at 0° C. was added NaH (60% mineral oil dispersion; 4.87 g, 122 mmol) slowly (CAUTION: GAS EVOLUTION). The reaction mixture was stirred at 0° C. for 2 h. Benzenesulfonyl chloride (17.0 ml, 132 mmol) was added dropwise, and the reaction mixture was allowed to warm to ambient. After 1 hour the reaction mixture was cooled in an ice bath, and 100 mL of water was added slowly (CAUTION: GAS EVOLUTION, EXOTHERM). The reaction mixture was partitioned between ethyl acetate (500 mL) and brine (600 mL). The organic layer was washed with additional brine (500 mL), followed by saturated aqueous ammonium chloride (250 mL). The first and 3rd aqueous layers were combined and back-extracted with ethyl acetate (500 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to a thick slurry. EtOAc (100 mL) was added, followed by hexanes (100 mL). The mixture was filtered, and the filter cake was rinsed with 1:1 EtOAc/Hexanes (50 mL) to afford 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a grey solid. The filtrate can be concentrated and purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford additional product. LRMS (ESI) calculated for C13H9BrN2O2S [M+H]+, 337.0; found 336.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 4 h
Yield: 81.7 %

Procedure:
The product from Step (c) (0.5 g, 1.94 mmol) was dissolved in methanol (50 ml) and treated with 5 wt % Palladium on charcoal (0.15 g). The reaction mixture was pressurized with 50 psi of H2 and stirred for 4 hours. The reaction was filtered and concentrated in vacuo to afford the title compound (0.36 g, 81%); MS (ES+) m/e 229 [M+H]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:23][CH:24]3[CH2:26][O:25]3)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3>CO>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:23][CH:24]([OH:25])[CH2:26][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: Sc1ccccc1
Solvent: CO
Product: OC(CSc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Benzenethiol (30 Tl, 0.29 mmol) was added to a solution of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (101.6 mg, 0.27 mmol) in 5.0 ml MeOH at r.t. The reaction mixture was heated to 80° C. and stirred overnight at the same temperature. The reaction was monitored by lc/ms for the consumption of SM. The reaction was cooled, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered and condensed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12].CO[CH:15]1[CH2:19][CH:18](OC)[CH2:17]O1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: COC1COC(OC)C1
Reactant: NCCCc1ccc(F)cc1F
Product: Fc1ccc(CCCn2cccc2)c(F)c1

Procedure:
17.1 g (0.10 mol) of 3-(2,4-difluorophenyl)propylamine are heated at 260° C. for 2 hours in an autoclave with 13.2 g (0.10 mol) of 2,4-dimethoxytetrahydrofuran. The reaction mixture is cooled and then purified by vacuum distillation. 10.6 g (48% of theory) of a colourless oil which boils at 80° C. and 0.2 mbar or 146°-147° C. and 15 mbar are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH3:20]
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-trifluoromethyl-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-trifluoromethyl-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. MS: m/e=277.2 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncnc2cc(N)ccc12
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A mixture of 600 mg of tert-butyl 7-nitroquinazolin-4-ylcarbamate and 150 mg of 10% Pd—C in 15 ml each of THF and MeOH was stirred overnight under a hydrogen balloon, filtered through a Celite® pad, concentrated and purified by chromatography eluting with 5% methanol in dichloromethane to provide 385 mg of tert-butyl 7-aminoquinazolin-4-ylcarbamate (compound 98-4). MS m/e=261.1 (MH+)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCc2cccc(Br)c2)CC1
Reaction time: 96 h
Yield: 92.2 %

Procedure:
To 3-(2-bromo-ethyl)-1-bromo-benzene (0.15 ml, 1 mmol), 1-tert-butoxycarbonyl-piperazine (186 mg) and potassium carbonate (280 mg), acetonitrile (4 ml) was added, followed by stirring for 4 days. To the reaction mixture, ethyl acetate was added, which was washed with ammonium chloride solution, followed by drying over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, to obtain 3-(2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethyl)-1-bromo-benzene as a colorless oil (340 mg, 92%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([NH:15][CH2:16][C:17]4[CH:18]=[C:19]([S:23]([CH3:31])(=[N:25]C(OCC)=O)=[O:24])[CH:20]=[CH:21][CH:22]=4)=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.ClCCl.CO>CO>[CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([NH:15][CH2:16][C:17]4[CH:18]=[C:19]([S:23]([CH3:31])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=4)=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(NC4CC4)ncnc3c2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=N)(=O)c1cccc(CNc2ccc3c(NC4CC4)ncnc3c2)c1
Yield: 74 %

Procedure:
According to GWP 6, conversion of (RS)-S-[3-({[4-(cyclopropylamino)quinazolin-7-yl]amino}methyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (58 mg, 0.13 mmol) and chromatographic purification (silica gel, n-hexane/ethyl acetate: 0→100% ethyl acetate, followed by dichloromethane/methanol: 0→25% methanol) gives the desired product in 74% yield (36 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.ClCCl.C(O)C.N>ClCCl.CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:4]2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCC1CN(C(=O)OCc2ccccc2)CCO1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: O=C(NCC1CN(C(=O)OCc2ccccc2)CCO1)Nc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 5 (2.0 g) in dichloromethane (100 ml) was added 4-chlorophenylisocyanate (1.35 g). The mixture was stirred at 22° C. for 18 h before 10% 0.880 ammonia solution in methanol (10 ml) was added. Stirring was continued for a further 30 min before the solvent was removed in vacuo. The residue was purified by Biotage flash chromatography on silica gel, eluting with 33% ethyl acetate/cyclohexane; further purification by Biotage flash chromatography on silica gel, eluting with 500:8:1 dichloromethane/ethanol/0.880 ammonia solution gave the impure title compound as a buff solid (3.6 g).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]=[CH2:12])[N:6]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:16])[CH:2]=[CH2:3].CCC(OO)=[O:20].C1C=CC=CC=1>>[CH2:1]([N:4]1[C:5](=[O:16])[N:6]([CH2:13][CH:14]2[O:20][CH2:15]2)[N:7]([CH2:10][CH:11]=[CH2:12])[C:8]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)n(CC=C)n(CC=C)c1=O
Reactant: CCC(=O)OO
Solvent: c1ccccc1
Product: C=CCn1c(=O)n(CC=C)n(CC2CO2)c1=O

Procedure:
6.895 kg (35 mol) of trisallylurazole were reacted with 31.5 kg of a 22% strength solution of perpropionic acid in benzene (77 mol) at 60° C. in a manner analogous to that described in Example 1. After a reaction time of 10 hours, the percarboxylic acid conversion was 97.2% and the conversion of trisallylurazole was 94.6%. Diallylglycidylurazole was formed in a selectivity of 28.3%, allyldiglycidylurazole was formed in a selectivity of 41.2% and trisglycidylurazole was formed with a selectivity of 20.1%, in each case based on the trisallylurazole reacted.
Reaction SMILES: [CH2:1]([N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([NH:8]C(OCC)=O)=[S:7])[CH:2]=[CH:3][CH3:4].C[O-].[Na+]>CO>[CH2:1]([N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([NH2:8])=[S:7])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCN(C(=S)NC(=O)OCC)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC=CCN(C(N)=S)c1cccc(C(F)(F)F)c1
Yield: 50.5 %

Procedure:
A solution of N-crotyl-N-(3-trifluoromethylphenyl)-N'-ethoxycarbonylthiourea (6 g) and sodium methoxide (28 % methanolic solution; 6.6 g) in methanol (100 ml) was refluxed for 2 days. After removal of the solvent, the residue was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give N-crotyl-N-(3-trifluoromethylphenyl)thiourea (2.4 g). The thus obtained thiourea (2.0 g) and N-bromosuccinimide (1.4 g) were dissolved in chloroform (50 ml), and the resultant solution was stirred at room temperature for 5 hours, washed with an aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure, the residue was subjected to column chromatography to give 0.8 g of 2-imino-3-(3-trifluoromethylphenyl)-5-(1-bromoethyl)thiazolidine.