Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[OH:13]
Reactant: [H][H]
Reactant: COc1cccc(CC(=O)c2ccco2)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CC(O)C2CCCO2)c1OC
Yield: 70.5 %

Procedure:
A solution of 450 mg(1.8 mmol) of 2-(2',3'-dimethoxyphenyl)-1-furanylethanone, from Step 2, and 20% palladium on carbon (225 mg) in 75 mL of methanol was shaken under 4 atmospheres of hydrogen until hydrogen uptake ceased. The solution was filtered and concentrated in vacuo to give 320 mg (69% yield) of the title compound as an oily solid. This product was carried on without purification to the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:13][O:14][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: NCc1ccc(OCCCl)cc1
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ccc(CN)cc1
Reaction time: 2 h

Procedure:
4-(2-Chloroethoxy)benzylamine (2.0 g; 0,11 mol) was dissolved in anhydrous toluene (50 ml). The reaction mixture was ice-cooled and sodium methoxide (0.59 g; 0.011 mol) dissolved in methanol (5 ml) was added thereto. When the addition was complete the mixture was left to stand for 2 hours at room temperature and filtered. Solvent was evaporated from the filtrate, to give an oily residue of good purity.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.Cl.[CH3:20][NH:21][CH3:22].C([O-])([O-])=O.[K+].[K+].C[N:30]([CH:32]=O)C>>[NH:30]1[C:32]2[C:10](=[C:5]([C:7]3[N:8]=[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:10]4[S:11][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[CH:4][C:5]=4[N:6]=3)[CH:4]=[CH:3][CH:2]=2)[CH:9]=[N:8]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C)C=O
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added dimethylamine hydrochloride (21 mg, 0.3 mmol) and K2CO3 (90 mg, 0.6 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 304 after reverse phase HPLC purification (34 mg). MS (Q1) 395 (M)+
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:25][CH2:26][CH2:27][Cl:28])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 80 °C
Reaction time: 18 h
Yield: 44.5 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.82 g, 2.7 mmol) in dry DMF (12 mL) is added 1-bromo-3-chloropropane (1.28 g, 8.1 mmol) and potassium carbonate (1.12 g, 8.1 mmol). The mixture is heated at 80° C. for 6 h. The mixture is then stirred at room temperature for 18 h followed by another 6 h at 80° C. The mixture is partitioned between water and CH2Cl2. The organic layer is washed 3 times with water (100 mL). The organic layer is then dried over anhydrous sodium sulfate and concentrated. Column chromatography (60 mL silica) using hexanes/CH2C2 (1:1) as eluent gave an oil which is rechromatographed (60 mL silica) using hexanes/CH2C2 (60/40) as eluent gave 0.454 g (44%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]2[N:18]=[N:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:24]=3)[N:21]=2)[C:6]1=[O:41].[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1[CH2:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(Cl)(Cl)Cl.CO>[ClH:1].[ClH:1].[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1[CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[CH:8]=[C:7]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]5[CH:40]=[CH:39][C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]=5)[CH:24]=4)[N:21]=3)[C:6]2=[O:41])[CH2:55][CH2:54]1
Reactant: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2CCCCl
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2CCCN1CCN(Cc2ccc3ccccc3n2)CC1
Product: Cl
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 182.9 %

Procedure:
A mixture of 1-(3-chloropropyl)-6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (179 mg, 0.316 mmol) and N-(2-quinolylmethyl)piperazine (287 mg, 1.26 mmol) was stirred under an argon flow at 120° C. for 2.5 hours. The mixture was allowed to cool, subjected to silica gel column chromatography (developer: chloroform-methanol (40:1)), and purified. Fractions including the target compound were collected, and concentrated under reduced pressure, to thereby obtain the free base of the title compound (219 mg, 0.289 mmol) as yellow oily matter. The thus-obtained free base of the title compound was dissolved in methanol (50 ml), and a solution of hydrochloric acid (4N) in ethyl acetate (144 μl, 0.576 mmol) was added to the resultant mixture. The mixture was crystallized from a methanol-diethylether mixture, to thereby obtain the title compound (184 mg, 0.22 mmol, 70.1%) as yellow powder.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([OH:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:12][S:13]([O:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCc2cccnc21
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCc2cccnc21
Reaction time: 8 h

Procedure:
To a stirred solution of 2.0 g (13 mmol) of 5,6,7,8-tetrahydroquinolin-8-ol and 3.3 g (27 mmol) of 4-(dimethylamino)pyridine in 30 mL of dichloromethane was added 1.3 mL (16 mmol) of methanesulfonyl chloride under an atmosphere of nitrogen. The reaction mixture was stirred for 8 h and then diluted with 30 mL water. The aqueous phase was then extracted with dichloromethane (3×30 mL) and the combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a light orange gum that was used without further purification. LC/MS: m/z (ES) 172.0 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ncoc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ncoc2c1

Procedure:
6-Methylbenzoxazole was reacted with NBS (1 eq) and catalytic amount of benzoyl peroxide in CCl4 at 90° C. for 12 h to obtain 6-bromomethylbenzoxazole which was purified by flash chromatography (EtOAc:Hexane=1:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:14]=2)[N:13]=1
Reactant: O=C(CC1CCCCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cc3nnc(CC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.9 %

Procedure:
To a suspension of N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide (46 mg, 0.1 mmol) in THF (2 mL) at room temperature was added diisopropylethylamine (0.14 mL, 0.8 mmol). After 5 min, triphenylphosphine dichloride (110 mg, 0.33 mmol) was added, and the reaction mixture stirred at room temperature for 16 h. Analysis by HPLC/MS indicated the reaction was complete. The reaction was diluted with EtOAc (40 mL), washed with H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated. The obtained residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-30%) in hexanes to yield 45 mg of the desired product with 80% purity (contaminated with triphenylphosphine oxide). The product was further purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100% B, 8 min gradient, 100% B hold for 7 min, (A 90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 30 mg (68%) of the title compound as a white powder. HPLC/S (method A): retention time=4.22 min, (M+H)+=437.1. 1H NMR (CDCl3, 400 MHz): δ 8.03 (s, 1H), 7.33-7741 (m, 4H), 7.21-7.28 (m, 2H), 7.07 (d, J=8.31 Hz, 2H), 3.14 (d, J=7.09 Hz, 2H), 2.01-2.12 (m, 1H), 1.69-1.80 (m, 4H), 1.21-1.29 (m, 3H), 1.10-1.17 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][NH2:21])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:22][C:23]1[CH:24]=[C:25]([C:29]2[N:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][N:30]=2)[CH:26]=[CH:27][CH:28]=1>C(OCC)(=O)C.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][NH:21][C:35]([C:32]2[CH:33]=[N:34][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)=[N:30][CH:31]=2)=[O:36])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium carbonate (13.94 mmol) and 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (4.65 mmol) in ethyl acetate (30 mL) and water (20 mL) is added a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (4.65 mmol) in ethyl acetate (20 mL). The mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated in vacuo to give 3-({[2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a solid. MS 415 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.47 (s, 9H), 1.55-2.22 (m, 5H), 2.90-4.90 (m, 6H), 7.15-7.25 (m, H), 7.41-7.53 (m, H), 7.56 (bs, NH), 8.18 (d, H), 8.29 (d, H), 9.21 (s, 2H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)OC1>O1CCOCC1.O.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>[CH3:44][N:43]1[C:39]([C:2]2[S:6][CH:5]=[C:4]([C:7]([NH:9][CH:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[CH:3]=2)=[CH:40][CH:41]=[N:42]1
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)c1csc(Br)c1)c1ccccc1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2ccccc2)cs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2-{[(5-bromo-3-thienyl)carbonyl]amino}-2-phenylethyl)carbamate (250 mg, 0.588 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (325 mg, 2.35 mmol), tetrakistriphenylphosphine Pd(0) (34 mg, 29.4 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 5 h, additional tetrakistriphenylphosphine Pd(0) (34 mg, 29.4 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol) were added. After 12 h, the reaction solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organics were dried (Na2SO4), concentrated under vacuum and purified on silica gel (1% MeOH in DCM) to give the title compound (250 mg, quant.) as an orange oil: LCMS (ES) m/z=427.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:13][C:14]3[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:24].[F:25][C:26]([F:40])([F:39])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:13][C:14]3[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:27][C:26]([F:40])([F:39])[F:25]
Reactant: Cc1cc(C)c(CN2CCOc3ccc(O)c(Cl)c3C2=O)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCOc3ccc(OCC(F)(F)F)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 150 °C
Yield: 14.6 %

Procedure:
A mixture of 6-chloro-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (124d, 100 mg, 0.287 mmol), toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (73.0 mg, 0.287 mmol), potassium carbonate (79.0 mg, 0.574 mmol), and anhydrous DMF (6 mL) was heated at 150° C. for 45 minutes in the microwave. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, MeOH/EtOAc) to give the title compound (Example 124, 18 mg, 16% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (br. s., 1H), 7.33 (d, J=8.93 Hz, 1H), 7.05 (d, J=8.93 Hz, 1H), 5.94 (s, 1H), 4.84 (q, J=8.60 Hz, 2H), 4.62 (s, 2H), 4.02 (br. s., 2H), 3.41 (br. s., 2H), 2.21 (s, 3H), 2.14 (s, 3H); MS 431.1 [M+1].
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][Si:11](Cl)([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2]/[C:3](/[O:9][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(/CCl)O[Si](C)(C)C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 4-chloro-3-oxobutanoic acid. methyl ester (60.4 g, 0.4 mol) and trimethylsilyl chloride (48.8 mL, 1.3 mol) in 500 mL dry ethyl acetate was cooled to -20° C. and triethylamine (17.42 mL, 1.25 mol) was added dropwise over 15 minutes under nitrogen atmosphere. The cold bath was removed and the heterogeneous mixture was stirred for two hours. The mixture was diluted with 200 mL dry hexane, stirred for five minutes and filtered under nitrogen. The filtrate was evaporated under vaccum. The product was redissolved in 100 mL hexane and filtered to remove a small amount of TEA.HCl. The filtrate was evaporated and the product was kept under pump vaccum for 0.5 hours to give the title compound (83.95 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:15])([F:14])[C:10](Br)([F:12])[F:11].CS(C)=O>[Cu].O>[F:14][C:9]1([F:15])[C:10]([F:12])([F:11])[C:2]2[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)c(Cl)c1
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)C(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Into a pressure bottle were placed 3.0 g (0.0085 mole) 3-chloro-4-(2-bromo-1,1,2,2-tetrafluoroethoxy)nitrobenzene, 2.7 g (0.043 mole) copper powder (200 mesh), and 40 ml of dimethyl sulfoxide. The pressure bottle was sealed, and the reaction mixture stirred at 190°-195° C. for 6.5 hours. The pressure bottle was cooled to room temperature, opened, and the contents poured into a separatory funnel. Approximately 200 ml of water was added to the separatory funnel, and the mixture was extracted with three 150 ml portions of diethyl ether. The extracts were combined and washed first with 200 ml of a 2N hydrochloric acid solution, then with 200 ml of a saturated aqueous sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, leaving an oil. The reaction described above was repeated one additional time. The residual oils from the two experiments were combined and upon standing formed crystals of 2,2,3,3-tetrafluoro-2,3-dihydro-5-nitrobenzofuran.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Nc1ccn(Cc2cccc(Cl)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4cccc(Cl)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-chloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C)C=O.O>[N:13]1([CH2:12][C:10]2[C:9]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:11]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 2-hydroxy-4-(morpholinomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 48; 300 mg, 0.94 mmol) was taken up in N,N-dimethylformamide (5 ml) and cesium carbonate (340 mg, 1.04 mmol) and benzyl bromide (0.16 ml, 1.31 mmol) were added. The mixture was heated at 40° C. for 18 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer was separated and washed with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (1:1 cyclohexane/ethyl acetate-10% 7M NH3 in methanol/dichloromethane) gave the title compound as oil. 248 mg.
Reaction SMILES: Br[C:2]1[C:13]([F:14])=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:4]([Cl:15])[CH:3]=1.CC(C)=O.C(=O)=O.[Li]CCCC.[O:28]=[C:29]1[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C1COCC1.CCOC(C)=O>[CH2:36]([NH:40][C:33]([CH:31]1[CH2:30][C:29]([C:2]2[CH:3]=[C:4]([Cl:15])[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:12][C:13]=2[F:14])([OH:28])[CH2:32]1)=[O:35])[CH:37]([CH3:39])[CH3:38]
Reactant: Fc1cc(CN2CCCC2)c(Cl)cc1Br
Reactant: CC(C)CN
Reactant: O=C1CC(C(=O)O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)CNC(=O)C1CC(O)(c2cc(Cl)c(CN3CCCC3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.4 %

Procedure:
To Intermediate 11, 1-(4-Bromo-2-chloro-5-fluorobenzyl)pyrrolidine (4.0 g, 13.7 mmol) in THF (34 mL) at −78° C. (acetone/dry ice bath) was added a solution of nBuLi (5.5 mL, 13.7 mmol, 2.5 M THF). After 15 min, a precooled (−78° C.) solution of 3-oxocyclobutanecarboxylic acid (0.78 g, 6.8 mmol, in 5 mL of THF) was added via cannula. The reaction was allowed to slowly warm to rt overnight. After approximately 16 h, isobutylamine (1.4 mL, 13.7 mmol) was added, followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in EtOAc, 6.6 mL, 10.2 mmol). After 1 hr the reaction was diluted with EtOAc and then quenched with 1N NaOH. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 120 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (400 mg, 15% yield) as a yellow foam: Rf=0.23 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C20H28Cl FN2O2, 382.9, found, 383, 385 (M+H) APCI; 1H NMR (300 MHz, CDCl3): δ 7.37 (d, J=7.0 Hz, 1H), 7.20 (d, J=11.6 Hz, 1H), 6.25-6.22 (bm, 2H), 3.68 (s, 2H), 3.09-2.84 (m, 5H), 2.57 (apt bs, 4H), 2.46-2.43 (m, 2H), 1.79-1.70 (m, 5H); 0.88 (d, J=6.6 Hz, 6H); 100 MHz 13C NMR (CDCl3) δ 177.5, 159.5 (d, JC-F=247.2), 138.3, 132.1, 128.2, 117.9 (d, JC-F=24.7 Hz), 73.2, 56.5, 54.3, 47.4, 40.1, 34.6, 28.7, 23.8, 20.3.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[Cl:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCOCC>[Cl:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CCCCC(=O)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(CCl)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 2.1 g. of magnesium and 20 mg. of mercuric chloride in 25 ml. of ether is added 0.8 ml. of propargyl bromide. After a few minutes of vigorous stirring, to this is added a mixture of 10.75 g. of 1-chloro-2-hexanone and 7.2 ml. of propargyl bromide in 25 ml. of ether, at such a rate that the reaction mixture is maintained at 25°-28° C. After addition, the mixture is stirred at room temperature one hour, cooled in a ice-water bath and 30 ml. of saturated ammonium chloride is added dropwise. The mixture is filtered through celite and washed with ether. The ether solution is concentrated to give 11.0 g. of a yellow liquid which is vacuum distilled to give 6.9 g. of product as a colorless liquid at b.p. 60°-61° C./4 mm.; PMR δ 3.62 (ABq, CH2Cl), 2.53 (d, J=3, C≡C--CH2), 2.06 (t, J=3, HC≡C).