Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[N:17][CH:18]=1)[CH2:6][CH2:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[N:17][CH:16]=[C:15]([CH2:19][C:20]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:21])[CH:14]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-acetic acid (50 mg, 0.16 mmol), HATU (122 mg, 0.32 mmol), Et3N (64 mg, 0.64 mmol) and morpholine (56 mg, 0.64 mmol) were dissolved in DCM (4.0 mL) and the resulting reaction mixture was stirred at room temperature overnight. After evaporating off the DCM, the residue was re-dissolved in EtOAc and was washed with brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give the title compound (8.5 mg, 13.9%) as light yellow oil. MS: 386.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:39]([NH2:42])([CH3:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:39]([NH:42][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:40])[CH3:41])[CH:36]=[CH:37][CH:38]=1
Reactant: COc1cccc(C(C)(C)N)c1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: COc1cccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c1
Yield: 64 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(3-methoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10b) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 64%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (325 mg, 2.37 mmol) from Step 2 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 100 mg, 2.49 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (600 mg, 2.61 mmol) from Step 4 of Example 36 in DMF (2 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (250 mL) and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (356 mg, 45%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.41 (t, J=2.0 Hz, 1H), 8.10 (dd, J=2.6, 9.4 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.3, 8.3 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COCCN
Product: COCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 93.5 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2-methoxyethyl amine (1.62 g, 22 mmol) to give the title compound (5.5 g, 95%) as an off-white crystalline solid. MS (ISP) 294.1[(M+H)+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH:10]([OH:16])[C:11](=[NH:15])[O:12]CC.C(N(CC)CC)C.[O:24]1CCC[CH2:25]1>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH:10]1[O:16][C:25](=[O:24])[NH:12][C:11]1=[O:15]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(F)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2c(F)cccc2Cl)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Ethyl 1-(2-chloro-6-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (15.0 g., 0.056 mole) and triethylamine (16.8 g., 23.3 ml., 0.167 mole) were taken into 560 ml. of tetrahydrofuran and cooled to 0° C. Phosgene was bubbled through the reaction mixture for 35 minutes. It was then stirred for 2.5 hours at room temperature, poured into 600 cc. of crushed ice and extracted with three portions of ethyl acetate. The combined extracts were washed with water, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to product (14.4 g.). Recrystallization from toluene afforded purified 5-(2-chloro-6-fluorophenyl)oxazolidine-2,4-dione [10.7 g., 83%; m.p. 153°-155° C.; ir (KBr) 1820, 1740 cm-1 ].
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCOCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
In a 25 mL pear shaped flask was placed 5-iodo-2′-deoxyuridine (0.354 g, 1.0 mmol), 2-trimethylstannylpyridine (0.84 g, 3.5 mmol), Bis (triphenylphosphine)-palladium (II) chloride (0.070 g, 0.1 mmol), and anhydrous 1,4-dioxane (15 mL). The reaction was heated at 60° C. for 15 hrs then at 90° C. for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (10% CH3OH in CH2Cl2 (1% NH3)) to yield 0.253 g (83%) of the title compound as a white solid m.p. 201-203° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.ClCCl>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:3]=1
Reactant: C#CCCO
Reactant: Brc1cnc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cnc2ccccc2c1
Yield: 136.9 %

Procedure:
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1 ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL of dichloromethane is degassed by bubbling dry nitrogen through it for 15 minutes, and 0.7 g (0.00I mol) of bis(triphenyl-phosphine)palladium dichloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate), and concentrated to give 27 g of a gold oil. The oil was triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7°-96.7° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[I-:10]>ClC1C=CC=CC=1>[I:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCBr
Reactant: [I-]
Solvent: Clc1ccccc1
Product: CCCCCCCCI

Procedure:
A reaction using the above reactor was conducted using the following chemistry. Bromooctane in the organic solvent chlorobenzene was reacted with aqueous iodide to form iodoctane in chlorobenzene and aqueous bromide ion. To ensure that this reaction required the use of a phase transfer catalyst, a brief dispersed-phase study was conducted. A solution 0.5 M in bromooctane and 0.1 M in tetradecane (as a gas chromatograph standard) in chlorobenzene was stirred with an equal volume of 2.0 M potassium iodide at 40 degrees C. for 4 hours. After this period, no iodooctane could be detected by gas chromatography. All analyses were conducted with a Perkin-Elmer 3920 gas chromatograph equipped with a flame ionization detector and a 10' by 1/8" OV-101 column at 200 degrees C. When this experiment was repeated using 0.05 M tetrabutylammonium bromide in the organic feed as a phase transfer catalyst, 50% conversion of bromooctane to iodoctane was observed after 4 hours. Because the organic-phase concentration of tetrabutylammonium iodide, the active form of the catalyst, remains constant with time under these reaction conditions, first-order kinetics with respect to the disappearance of bromooctane is predicted by the phase transfer catalysis mechanism. This effect was observed in these experiments.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH3:11])=[CH:5][CH:4]=1.[Br:20]Br>ClCCCl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:10]([Br:20])[CH3:11])=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CC=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: ClCCCl
Product: COc1ccc(C(=C(C)Br)c2ccc(OC)cc2)cc1
Temperature: -20 °C
Yield: 99.6 %

Procedure:
Into a reactor were introduced 2.50 g (9.82 mmol) of the 1,1-bis(4-methoxyphenyl)propene and 25 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to −20° C. A mixture of 1.57 g (9.82 mmol) of bromine and 13 mL of 1,2-dichloroethane was gradually added dropwise thereto, and the resultant mixture was stirred overnight at room temperature. This reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure to obtain 3.26 g (100%) of the target compound as a light-yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: O=C(O)c1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-carboxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 28.9, 32.0, 42.6, 60.5, 127.2, 127.4, 127.7, 130.2, 130.5, 140.1, 142.7, 142.7 and 167.0.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:24])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])([OH:3])=O.S(Cl)([Cl:27])=O>ClC(Cl)C>[Cl:27][C:10]1([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:3])[O:24]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=O)c1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc21

Procedure:
In 15 ml of dichloroethane was dissolved 580 mg of Compound (97), followed by addition of 0.58 ml of thionyl chloride. The mixture was heated for one hour under reflux. The solvent was evaporated off, and the residue was treated with isopropylether to give 500 mg of the subject Compound (98) as colorless crystals, m.p. 132°-134° C.
Reaction SMILES: OC([C:5]1[N:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1)(C)C.[Cl:22]C1C=CC(B(O)O)=CN=1>>[Cl:22][C:5]1[N:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Product: NC(=O)c1cc(-c2ccc(Cl)nc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (2.0 g, 7.97 mmol) and 2-chloro-5-pyridine boronic acid (1.25 g, 7.97 mmol) according to the general procedure described in Intermediate 10 Step 5.
Reaction SMILES: [Na+:1].[Na+].[Na+].[Na+].[Na+].[Na+].[N+:7]([C:10]1[CH:11]=[C:12]([C:51]([NH:53][C:54]2[CH:55]=[C:56]([C:61]([NH:63][C:64]3[C:73]4[C:72]([S:74]([O-:77])(=[O:76])=[O:75])=[CH:71][C:70]([S:78]([O-:81])(=[O:80])=[O:79])=[CH:69][C:68]=4[C:67]([S:82]([O-:85])(=[O:84])=[O:83])=[CH:66][CH:65]=3)=[O:62])[CH:57]=[CH:58][C:59]=2[CH3:60])=[O:52])[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:26]([NH:28][C:29]3[C:38]4[C:37]([S:39]([O-:42])(=[O:41])=[O:40])=[CH:36][C:35]([S:43]([O-:46])(=[O:45])=[O:44])=[CH:34][C:33]=4[C:32]([S:47]([O-:50])(=[O:49])=[O:48])=[CH:31][CH:30]=3)=[O:27])[CH:22]=[CH:23][C:24]=2[CH3:25])=[O:17])[CH:15]=1)([O-])=O>[Pd].O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[Na+:1].[Na+:1].[NH2:7][C:10]1[CH:11]=[C:12]([C:51]([NH:53][C:54]2[CH:55]=[C:56]([C:61]([NH:63][C:64]3[C:73]4[C:72]([S:74]([O-:77])(=[O:75])=[O:76])=[CH:71][C:70]([S:78]([O-:81])(=[O:80])=[O:79])=[CH:69][C:68]=4[C:67]([S:82]([O-:85])(=[O:84])=[O:83])=[CH:66][CH:65]=3)=[O:62])[CH:57]=[CH:58][C:59]=2[CH3:60])=[O:52])[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:26]([NH:28][C:29]3[C:38]4[C:37]([S:39]([O-:42])(=[O:40])=[O:41])=[CH:36][C:35]([S:43]([O-:46])(=[O:45])=[O:44])=[CH:34][C:33]=4[C:32]([S:47]([O-:50])(=[O:48])=[O:49])=[CH:31][CH:30]=3)=[O:27])[CH:22]=[CH:23][C:24]=2[CH3:25])=[O:17])[CH:15]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)cc1NC(=O)c1cc(C(=O)Nc2cc(C(=O)Nc3ccc(S(=O)(=O)[O-])c4cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c34)ccc2C)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)cc1NC(=O)c1cc(N)cc(C(=O)Nc2cc(C(=O)Nc3ccc(S(=O)(=O)[O-])c4cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c34)ccc2C)c1
Yield: 536.2 %

Procedure:
A mixture of 1.98 g of the product of Example 1, 60 ml of water and 500 mg of 10% palladium-on-carbon catalyst is hydrogenated in a Parr shaker. The resulting mixture is filtered, and the filtrate is evaporated. The residue is dissolved in 12 ml of hot water and 125 ml of absolute ethanol is added. The precipitate is collected, washed with ethanol and ether and dried to yield 1.73 g of the product of the Example.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12>C1COCC1>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:47]3[C:43](=[O:53])[C:44]4[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:46]3=[O:48])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
20.3 g (65.6 mmol) 3-(1-diphenylmethylpiperidin-4-yl)-propan-1-ol, 17.2 g (65.6 mmol) triphenylphosphine and 9.7 g (65.6 mmol) phthalimide are suspended in 220 ml THF and a solution of 10.4 ml (65.6 mmol) azodicarbonic acid diethyl ester in 50 ml THF is added dropwise within one hour under protective atmosphere and light cooling (ca. 15-25° C.). After a further three hours, the solvent is removed under vacuum and the residue is crystallized from 60 ml 1-chlorobutane. Yield: 12.9 g (45%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13](Cl)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:20][CH2:19][CH:18]=[CH:17]1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([N:16]3[CH2:20][CH:19]=[CH:18][CH2:17]3)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cc2ncnc(Cl)c2cc1Cl
Reactant: C1=CNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc2ncnc(Cl)c2cc1Cl)N1CC=CC1

Procedure:
Prepared analogously to Example 2c from 4,6-dichloro-quinazoline-7-carboxylic acid chloride, pyrroline and sodium hydroxide solution in dichloromethane
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[O:18]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:19])[N:1]1[CH:2]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: NC(CC(=O)O)c1ccc(F)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C
Reaction time: 0.5 h

Procedure:
2.0 g of rac-3-amino-3-(4-fluorophenyl)propanoic acid (10.92 mmol) and 1.62 g of phthalic anhydride (10.92 mmol) were dissolved in 9 ml of DMF and heated at reflux at 135° C. overnight. The reaction solution was added to about 200 ml of water. The solid formed was stirred at RT for about 30 min and then filtered off, washed with water and dried under high vacuum. This gave 3.43 g of the title compound (86% of theory, purity about 86%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)C>[C:16]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)Cc1c(Cl)ncnc1N(C)C
Reactant: CC(C)(C)c1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cc1c(Oc2cccc(C(C)(C)C)c2)ncnc1N(C)C
Yield: 87.4 %

Procedure:
A mixture of methyl 4-chloro-6-dimethylamino-pyrimidin-5-yl-acetate (22.9 g, 100 mmol), 3-tert.butylphenol (15.0 g, 100 mmol), potassium carbonate (20.7 g, 150 mmol) and a catalytic amount of 18-crown-6 is heated in dimethylformamide (50 ml) at 130° C. for 6 hours. The reaction mixture is diluted with diethyl ether, washed with 2n NaOH and brine, dried (MgSO4) and evaporated to give methyl 4-(3-tert.butylphenoxy)-6-dimethylamino-pyrimidin-5-yl-acetate as a yellow oil (30 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](I)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:11]
Reactant: CCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (3.0 g, 24.6 mmol), ethyl iodide (5.9 ml, 73.8 mmol) and K2CO3 (3.4 g, 24.6 mmol) in 50 ml of acetone was stirred at +40° C. for 6 h and at RT overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15:100) to give 3-ethoxybenzaldehyde.
Reaction SMILES: [BrH:1].[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrBr.O>C(O)=O>[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:1])[CH:17]=2)[O:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CNC[C@H]2CCc3ccccc3O2)cc1
Reactant: Br
Agent: BrBr
Solvent: O
Solvent: O=CO
Product: Brc1ccc2c(c1)CC[C@H](CNCc1ccccc1)O2
Temperature: 16 °C
Reaction time: 1.17 h
Yield: 84.3 %

Procedure:
In a 30 L reaction vessel, N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrobromide (2173 g, 6.5 moles, 1.0 eq.) was suspended in 11.4 L formic acid. The suspension was cooled to 16° C., then bromine (1071 g, 6.7 moles, 1.03 eq.) was added over a 60 minutes, maintaining the reaction temperature between 15 and 16° C. After 70 minutes, a HPLC probe indicated the reaction to be complete. To the reaction mixture was then added 15.6 L water (temperature increased to 21° C.). The light reaction mixture was then stirred for 30 minutes at room temperature, then the product was filtered and washed with 3.9 L water. The 3.14 kg of light gray moist product was then suspended in 9.75 L dichloromethane. To this suspension was added 13 L 1M NaHCO3. Foaming ensued and the suspension became a bi-phasic solution. The aqueous phase was separated (14.5 L; pH=8) and the organic phase was washed with 6.5 L water. The phases were separated and the organic phase evaporated at 45° C. to yield 1820 g of N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amine.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30.0 g (155 mmol) of 2,3,4,5-tetrafluorobenzoic acid in 75 ml of dichloromethane was added 14.8 ml (1.1 equivalents) of oxalyl chloride. The mixture was then treated with three drops of dry N,N-dimethylformamide and the vigorous reaction was stirred at room temperature overnight. The mixture was then concentrated to an oil, taken up in toluene, and reconcentrated to afford 2,3,4,5-tetrafluorobenzoyl chloride which was used in the next step.