Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[O:3]C1>C(O)C.O.Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][C:7]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ccc(C2OCCO2)cc1Oc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 90.7 %

Procedure:
A solution of 26 g (0.1 mol) of 4-fluoro-3-phenoxy-benzaldehyde ethyleneacetal in 60 ml of ethanol, 20 ml of water and 1 ml of concentrated hydrochloric acid was stored at room temperature for 3 hours. The ethanol was then distilled off in vacuo, and 100 ml of toluene were added to the residue. The water was separated off and the organic phase was washed twice with 50 ml of water each time, dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 19.6 g (91% of theory) of 4-fluoro-3-phenoxy-benzaldehyde were obtained in this manner in the form of a colorless oil with a boiling point of 102°-104° C. /0.1 mm Hg.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:30])[N:4]([C:22]2[C:27](F)=[CH:26]C=CC=2F)[C:5]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[NH:32][CH3:33].[CH2:34]1COC[CH2:35]1>>[Br:1][C:2]1[C:3](=[O:30])[N:4]([CH2:22][C:27]2[CH:26]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([CH2:18][N:19]([CH3:20])[CH3:21])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: C1CCOC1
Reactant: CN(C)Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: CNC
Product: CN(C)Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccnc1

Procedure:
The title compound was prepared in a similar manner to the procedure outlined below for 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(dimethylamino) -methyl]pyridin-2(1H)-one using the aldehyde (300 mg, 0.85 mmol) described above and 2.0 N THF solution of dimethylamine (500 μL, 1 mmol) to give 110 mg (34%) of a colorless oil. The oil was then dissolved in MeOH (1 mL) and stirred with fumaric acid (25 mg) for 1 h. The resulting precipitate was filtered, washed with diethyl ether, and dried to give the pure product as it's fumurate salt. 1H-NMR (DMSOd6/400 MHz). δ 8.43-8.41 (m, 1H), 8.35 (s, 1H), 7.67-7.61 (m, 1H), 7.44-7.40 (m, 1H), 7.35-7.29 (m, 2H), 7.17-7.12 (m, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 5.41 (s, 2H), 5.32 (s, 2H), 3.13 (s, 2H), 2.12 (s, 6H). LC/MS, tr=1.55 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 464 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O.[CH:26]1([C:32]([OH:34])=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH:35](N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:26]1([C:32]([NH:23][C:3]2[CH:4]=[C:5]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:35])=[O:21])[CH:14]=4)[NH:9]3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CCCCC1
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1ccc(F)c([N+](=O)[O-])c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCCCC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To an ice-cold mixture of 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.3 mmol, 1.0 eq.), cyclohexanecarboxylic acid (0.46 mmol, 1.5 eq.), N,N-diisopropylethylamine (0.6 mmol, 2.0 eq.) in dichloromethane (5 mL) was added a solution of phosphorus oxychloride (0.36 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 2.5 hours. LC-MS indicated that the starting material was consumed completely. The reaction was quenched by 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layer was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-(cyclohexanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; Yield: 86%; MS (ESI+APCI) M+1=439.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[S-:13][C:14]#[N:15].[NH4+].[NH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:20][CH:19]=1>CC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:14]([NH:15][C:10]([C:2]2[O:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=2)=[O:11])=[S:13])=[CH:30][CH:29]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cc2cnccc2o1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCCCOC(=O)c1ccc(NC(=S)NC(=O)c2cc3cnccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Furo[3,2-c]pyridine-2-carbonyl chloride (161 mg, 1 mmol) is added to a solution of ammonium thiocyanate (200 mg, about 3 mmol) in acetone (5 ml) and stirred at room temperature for 1 hour. Butyl 4-aminobenzoate (180 mg, 0.93 mmol) is added to the reaction mixture. Stirring is continued overnight at room temperature. Solvent is evaporated to dryness and the residue diluted with 10% aqueous NaHCO3. The product is filtered, washed with water and methanol, and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1.[OH2:22]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])(=[O:19])=[O:22])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Br)cc1Cl
Reactant: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 31 %

Procedure:
Dissolve 4-bromo-2-chloro-1-methylsulfanyl-benzene (4.8 g, 20 mmol) and mCPBA (20 g, 80 mmol) in dichloromethane (100 mL). Stir for 2 hours. Dilute with dichloromethane (300 mL) and water (100 mL). Separate the organic layer and wash with aqueous saturated NaHCO3 (2×100 mL) and brine (100 mL). Dry with MgSO4, filter and concentrate in vacuo. Wash the solid with ether (2×14011) and dichloromethane (10 mL) to give 1.7 g of the title compound (31%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[C:32]2=[O:48]>>[C:38]([NH:37][C:34]1[N:33]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:32](=[O:48])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1-c1cccnc1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(-c5cccnc5)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 73.1 %

Procedure:
Argon was bubbled into a slurry of potassium carbonate (Mallinkrodt; 0.074 g, 0.536 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium(ii) (Aldrich; 4.74 mg, 6.70 μmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.070 g, 0.268 mmol), 8-bromo-2-(tert-butylamino)-3-(pyridin-3-yl)quinazolin-4(3H)-one (404a; 0.050 g, 0.134 mmol) for 1 min. The reaction was sealed and heated to 80° C. for 30 min. The reaction was adsorbed onto 0.7 g silica gel and dried in vacuo. The material was treated with purified by silica gel chromatography (12 g column) using 0-100% (90/10 DCM/MeOH) in DCM. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(pyridin-3-yl)quinazolin-4(3H)-one (0.042 g, 0.098 mmol, 73% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (1H, s), 8.74 (1H, dd, J=4.9, 1.6 Hz), 8.64 (1H, d, J=2.2 Hz), 7.91-7.99 (2H, m), 7.89 (1H, dd, J=7.8, 1.6 Hz), 7.59-7.69 (2H, m), 7.24 (1H, t, J=7.6 Hz), 6.77 (1H, d, J=1.6 Hz), 4.61 (1H, s), 4.49-4.58 (1H, m), 1.31-1.41 (12H, m). m/z (ESI, +ve ion) 429.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC.CCOCC.O>CN(C=O)C.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]=[CH2:11])=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=Cc1ccc(Br)c(F)c1
Yield: 53.9 %

Procedure:
A solution of 1-bromo-2-fluoro-4-iodo-benzene (1 g, 3.32 mmol), tributyl(vinyl)tin (0.97 mL, 3.32 mmol) and dichlorobis(triphenylphosphine)palladium(II) (116 mg, 0.17 mmol) in anhydrous DMF (3 mL) was heated in a microwave reactor to 160° C. for 5 minutes. Ether (20 mL) and H2O (5 mL) were added and partitioned. The organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel eluting with hexanes to provide the title compound as a colorless oil (360 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 5.33 (d, J=9 Hz, 1 H), 5.76 (d, J=18 Hz, 1 H), 6.63 (dd, J=18 Hz, J=9 Hz, 1 H), 7.05 (dd, J=9 Hz, J=1 Hz, 1 H), 7.16 (dd, J=9 Hz, J=1 Hz, 1 H), 7.49 (t, J=9 Hz, 1 H); (DCl/NH3) m/z 201 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.Cl>O1CCCC1>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reaction time: 4 h
Yield: 36.8 %

Procedure:
In a 300 mL three-neck flask, 410 mg (17 mmol) of active magnesium was stirred in 5 mL of dehydrated tetrahydrofuran (THF), and about 0.2 mL of 1,2-dibromoethane was added thereto, so that bubble release and heat generation were confirmed. A solution in which 5.2 g (15 mmol) of 4-bromophenyl-1-phenyl-1H-benzimidazole has been dissolved in 50 mL of dehydrated THF was added thereto. The mixture was heated and stirred for 4 hours, and then cooled to room temperature, so that a Grignard reagent was prepared. Then, in a 500 mL three-neck flask were put 3.7 g (17 mmol) of 4-bromobenzoyl chloride and 150 mL of dehydrated THF, and the mixture was stirred at −40° C. The above Grignard reagent was dropped into the mixture, the mixture was stirred for 1 hour, and then stirred at room temperature for about 15 hours. After reaction, 1N-hydrochloric acid was added to the mixture until the mixed solution became acid. An organic phase of the obtained mixed solution was washed with water, and then magnesium sulfate was added thereto so that moisture was adsorbed. This suspension was filtered, the resulting filtrate was concentrated, and ethyl acetate and toluene were added to perform recrystallization. As a result, 2.5 g of powder was obtained. The reaction scheme is shown in (A-1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=O)[CH3:19].C(=O)([O-])[O-]>C(Cl)Cl>[Cl:17][C:15]1[CH:16]=[C:11]2[C:12]([C:18]([CH3:19])=[CH:2][C:1]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:10]2)=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1N
Reactant: CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 60 h

Procedure:
Acetophenone (0.66 mL, 5.69 mmol) was added to 1-(2-amino-4-chlorophenyl)ethanone (0.868 g, 5.69 mmol) and [Hbim]BF4 (1.50 g, 7.08 mmol) under Ar. The reaction mixture was heated at 100° C. for 57 h then cooled to rt and partitioned between EtOAc and H2O. The aq layer was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography on SiO2 (70 g, EtOAc in hexanes 0:100→1:40→1:30) afforded a lightly colored oil. The material was dissolved in DCM (100 mL) and stirred with PS-Ts-NHNH2 (2.07 g, 2.87 mmol/g, 5.94 mmol) for 2.5 d at rt and then with MP-carbonate (˜0.25 g, 2.74 mmol/g, 0.68 mmol) for 4 h. The resins were removed by filtration through Celite. The residue and Celite were rinsed with DCM multiple times. The filtrate was concentrated under reduced pressure to provide the title compound as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.18-8.12 (m, 3H), 7.92 (d, J=8.4 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.54-7.46 (m, 4H), 2.75 (s, 3H); MS (ES+): m/z 254.24 (35) [MH+]; HPLC: tR=3.82 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:17]=[C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:19][CH:20]=3)[C:13]([C:29](N(OC)C)=[O:30])=[N:12]2)=[CH:8][CH:7]=1>C1COCC1.CCOC(C)=O.Cl>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:17]=[C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:19][CH:20]=3)[C:13]([C:29](=[O:30])[CH3:1])=[N:12]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(=O)N(C)OC)n2)cc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(C)=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
According to Scheme 5, Step 5: Methylmagnesium bromide 3 M (148 μmol, 49 μL) was added dropwise at room temperature to a solution of 1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide (99 μmol, 46 mg) in THF (0.5 mL) and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with EtOAc and with an aqueous solution of HCl 1M. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4, was filtered and was concentrated to yield 1-(1-(4-methoxybenzyl)-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone (0.10 mmol, 42 mg, 100%) as a beige solid. The mixture was used without further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16].C1COCC1.[Br:22]Br>O>[Br:22][C:11]1[C:10]([Cl:9])=[C:15]([Cl:16])[CH:14]=[CH:13][N:12]=1
Reactant: BrBr
Reactant: Clc1ccncc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccnc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide (7.0 mL, 2.0 M heptane/THF, 14.0 mmol) was added to a solution of 3,4-dichloropyridine (1.88 g, 12.7 mmol) and anhydrous THF (30 mL) at −78° C. under N2. After 1 h, bromine (0.71 mL, 14.0 mmol) was added. After an additional 30 min, the reaction was allowed to warm to rt and maintained for 30 min. The mixture was poured into water, extracted with EtOAc, dried, filtered, concentrated, and purified by silica gel chromatography (0→30% EtOAc/hexanes) to give 2-bromo-3,4-dichloropyridine after recrystallization from methanol. MS (ESI): 225.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10]O)[C:4]=1[CH3:12].S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Cl:15][CH2:10][C:5]1[C:4]([CH3:12])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=1
Reactant: COc1c(C)cnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)cnc(CCl)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
To a solution of 4-methoxy-3,5-dimethylpyridinemethanol (25.1 g, 0.15 mol) in dichloromethane (400 mL) was added a solution of thionyl chloride (18.8 g, 0.158 mol) in dichloromethane (100 mL) over 30 min at room temperature under argon. After an additional 30 min of stirring at room temperature, the solvent was removed under reduced pressure. The solid residue was suspended in hexanes (200 mL) and filtered. The solid was washed with hexanes (50 mL) and air-dried to give 33.3 g (100%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)=[N:28][C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:27]([C:35]3[CH:42]=[CH:41][C:38]([CH2:39][N:16]4[CH2:17][CH2:18][CH:13]([C:11]5[N:12]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=6)[NH:9][N:10]=5)[CH2:14][CH2:15]4)=[CH:37][CH:36]=3)=[N:28][C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)=[CH:24][CH:25]=1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccc(F)cc5)cc4)CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
219 mg (0.69 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 5.4 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.63 mmol) 4-[6-(4-Fluorophenyl)imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 147 mg (0.69 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is treated with saturated NaHCO3 and stirred for 20 minutes. The precipitate is filtered off, washed with water and dried. 233 mg (62.6%) of the desired product are obtained. 100 mg of this material are further purified by HPLC yielding 74.3 mg of the title compound as formiate.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: COc1ccc(CCN)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Methoxy-phenyl)-ethylamine. MS (ESI): 463.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:24][N:25]([CH3:27])[CH3:26])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reaction time: 2 h

Procedure:
A suspension of 16.5 g of ethyl 3-(2,7-dichloro-6-fluoro-3-quinolyl)-3-oxopropionate in 160 cm3 of ethyl acetate and 19 cm3 of N,N-dimethylformamide dimethyl acetal is heated at a temperature close to 75° C., with stirring, for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at 50° C. The dry extract is taken up in 50 cm3 of diisopropyl ether, drained and washed with twice 10 cm3 of diisopropyl ether. 16.57 g of ethyl 2-(2,7-dichloro-6-fluoro-quinoline-3-carbonyl)-3-dimethylaminoacrylate are obtained in the form of an orange solid melting at 122° C. This product is used for the subsequent steps without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cccn2-c2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1

Procedure:
To a solution of 5 mmol of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15][CH2:16]C)([CH2:10][CH2:11]CC)[CH2:6]CCC.[F-:18].C1C[O:22]CC1>>[F:18][CH2:11][CH:10]1[N:5]([CH3:6])[C:14](=[O:22])[CH2:15][CH2:16]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [F-]
Reactant: C1CCOC1
Product: CN1C(=O)CCC1CF

Procedure:
5-Hydroxymethyl-1-methyl-2-pyrrolidinone (see step 2 of Example 1B) and trifluoromethanesulfonic anhydride are reacted in CH2Cl2 and pyridine at 0° C. to give the trifluoromethylsulfonate ester, which is treated with TBAF in THF solution to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N1CCN(C2C=C(N[C:29]([C:31]3[C:32]4[N:33]=[CH:34][CH:35]=[N:36][C:37]=4[C:38]([C:41]4[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=4[Cl:49])=[CH:39][CH:40]=3)=[O:30])C=CC=2)CC1)C>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:29]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[C:38]([C:41]3[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=3[Cl:49])=[CH:39][CH:40]=2)=[O:30])=[CH:8][CH:7]=1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1
Reactant: CN(C)CCOc1ccc(N)cc1
Product: COc1ccc(Cl)c(-c2ccc(C(=O)Nc3ccc(OCCN(C)C)cc3)c3nccnc23)c1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63). Title compound: ESI-MS: 476.9 [M]+; tR=3.43 min (System 3).
Reaction SMILES: [BrH:1].Br.[NH2:3][CH2:4][C:5]#[C:6][CH2:7][NH:8][C:9](=[NH:12])[CH2:10][F:11].N(CC#CCN[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[N+]=[N-].Br.C(SC(=N)CF)C1C=CC=CC=1>>[BrH:1].[CH2:24]([O:23][C:21]([NH:3][CH2:4][C:5]#[C:6][CH2:7][NH:8][C:9](=[NH:12])[CH2:10][F:11])=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: N=C(CF)NCC#CCN
Reactant: CCCCOC(=O)NCC#CCN=[N+]=[N-]
Agent: Br
Agent: N=C(CF)SCc1ccccc1
Product: CCCCOC(=O)NCC#CCNC(=N)CF

Procedure:
1-Amino-4-(1-imino-2-fluoroethylamino)but-2-ynedihydrobromide was made from 1-azido-4-(butoxycarbonylamino)but-2-yne and S-benzyl-2-fluorothioacetimidate hydrobromide to yield 1-butoxycarbonylamino-4-(1-imino-2-fluoro-ethylamino) but-2-yne hydrobromide as an intermediate.