Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)=O>[CH:5]([NH:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:7]
Reactant: Nc1ccccc1CCc1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ccccc1CCc1ccccn1
Temperature: 25 °C
Yield: 83 %

Procedure:
An aceticformic anhydride mixture is prepared by mixing acetic anhydride (140 ml.) and formic acid (70 ml.). To this mixture, 2-(o-aminophenethyl)pyridine (59 g., 0.3 mole) is added in one portion with vigorous stirring at 25°C. After 15 minutes the solution is diluted with 450 ml. of water and concentrated in vacuo. The resulting residue is taken up in 1 liter of water and made basic with 50% sodium hydroxide. The basified solution is extracted with chloroform, the chloroform extract washed with water, dried over magnesium sulfate and the chloroform solvent evaporated. Crystallization of the residue from isopropyl acetate provides 57 g. (83% yield) of 2-(o-formamidophenethyl)pyridine melting at 78°-81°C. (uncorrected). An analytical sample (from isopropyl acetate) has a melting point of 83°-83.5°C. (corr.).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])=[CH:11][S:12][CH:13]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])=[CH:11][S:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cscc1C(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cscc1C(=O)Nc1ccccc1
Yield: 102.3 %

Procedure:
4-(tert-butoxycarbonylamino)-N-phenylthiophene-3-carboxamide (300 mg, 0.94 mmol) in CH2Cl2 (3 ml) was treated with TFA (0.36 ml, 4.71 mmol) at room temperature for 2.5 hours. The solvent was evaporated, the residue was dissolved in methanol/HCl, ether was added to the solution, the precipitate was recovered to give title compound (210 mg, 87%) which was used as is in the next step.
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.O(C)[Na]>[OH-].[Na+].CO>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:4]1[CH:5]=[CH:6][C:7](=[CH:13][C:9]2[NH:8][CH:12]=[CH:11][CH:10]=2)[S:1]1(=[O:3])=[O:2]
Reactant: O=Cc1ccc[nH]1
Reactant: O=S1(=O)CC=CC1
Agent: CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S1(=O)C(=Cc2ccc[nH]2)C=CC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
About 20 mmol (2.36 g) of 3-sulfolene (MW=118) and 42 mmol (4 g) of pyrrole-2-aldehyde (MW=95) were dissolved in an alkaline solution of 1.5 g of NaOH and 1.9 g of NaOCH3 in 70 ml of methanol. The mixture was stirred at room temperature for 5 days. The black-brown reaction mixture was concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)CCC.[F-].[NH4+]>C1COCC1.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>[NH2:1][C:2]1[C:12]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1c(-c2cccs2)cc(Br)c2c1C(=O)NC2=O
Yield: 87.3 %

Procedure:
3-Amino-4-iodo-6-bromophthalimide (100 mg, 0.273 mmol) was dissolved in THF (5 mL), and the solution was added with 2-(tributylstannyl)thiophene (0.173 mL, 0.546 mmol) and bis(triphenylphosphine)dichloropalladium (15 mg, 0.022 mmol), followed by stirring under reflux for 12.5 hours under argon atmosphere. The reaction mixture was added with 10% aqueous ammonium fluoride solution, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using hexane, then purified by preparative thin-layer chromatography (chloroform/acetonitrile=30/1) to obtain 3-amino-4-(thiophen-2-yl)-6-bromophthalimide (77 mg, yield 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][OH:20])=[N:14][CH:15]=3)[N:10]([CH3:21])[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[NH:33][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][O:20][C:34](=[O:35])[NH:33][C:24]4[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=4[F:22])=[N:14][CH:15]=3)[N:10]([CH3:21])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCO)nc21
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cn1nc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2cnc(NCCOC(=O)Nc3cc(C(F)(F)F)ccc3F)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (25.4 mg, 0.1 mmol) in N-methylpyrrolidinine (0.5 mL) was added 2-fluoro-5-trifluoromethyl-phenyl isocyanate (22 mg, 0.11 mmol, 2.1 eq). The reaction mixture was stirred for 1 hour at room temperature while monitored by TLC. The mixture was then evaporated and the crude product was purified by preparative HPLC to give pure (2-fluoro-5-trifluoromethyl-phenyl)-carbamic acid 2-(3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-phenyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethyl ester; 1H-NMR (DMSO): δ 3.71 (m, 2H), 3.81 (s, 3H), 4.34 (m, 2H), 7.41–7.60 (m, 4H), 7.92 (d, 2H, J=8.4 Hz), 8.11 (br s, 1H), 8.63 (s, 1H), 8.94 (s, 1 H), 9.15 (s, 1H), 9.36 (br s, 1H), 9.75 (br s, 1H); LC/MS (m/e)=695.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=O)=[CH:19][CH:18]=2)[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][CH:22]=2)[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=CCCc1ccc(N(Cc2ccc(O)cc2)S(=O)(=O)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(O)cc1)c1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of N-(4-hydroxy-benzyl)-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.093 g, 0.24 mmol) in 1.5 mL methylene chloride was added pyrrolidine (0.034 g, 0.47 mmol) and NaB(OAc)3H (0.092 g, 0.44 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure chromatography (10% methanol/methylene chloride) afforded 0.053 g (50%) of the title compound. MS 451.1 (M+1)+
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OC[C@H](C)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 3.01 g of (S)-(+)-1-acetoxy-3-bromo-2-methyl-propane (15.7 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. Stirring was continued for 2 h at 95-105° C. The dimethylformamide was removed by evaporation under reduce pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give the crude product as a brownish oil (5.81 g).
Reaction SMILES: [F:1][C:2]1([C:12](OCC)=[O:13])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1([CH2:12][OH:13])[CH2:3][CH2:4][N:5]([CH:8]2[CH2:9][O:10][CH2:11]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(C2COC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(F)CCN(C2COC2)CC1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 517A (0.59 g) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (1.8 mL) at 0° C. The reaction was removed from the ice bath and allowed to warm to room temperature. The reaction was quenched by the dropwise addition of 0.6 mL of water followed by 0.2 ml of 2N aqueous NaOH. The reaction was filtered through diatomaceous earth, rinsed with ethyl acetate (50 mL) and concentrated. Silica gel chromatography over silica gel (Reveleris 40 g) eluting with a gradient of 0.75% to 7.5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[NH:6][N:5]=1
Reactant: BrBr
Reactant: Cc1[nH]ncc1-c1ccccc1
Solvent: CC(=O)O
Product: Cc1[nH]nc(Br)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 5-methyl-4-phenyl-1H-pyrazole (3.0 g, 18.96 mmol) in acetic acid (glacial, 100 mL) was added bromine (1.457 mL, 28.4 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After quenched with aqueous solution of Na2SO3 (10% wt aq., 10 mL), the reaction was concentrated and extracted with EtOAc, washed with brine, dried over MgSO4, and purified by silica gel column chromatography to give the title compound as yellow oil (2.8 g). LCMS m/z=236.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 7.24-7.54 (m, 5H), 13.13 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]2[C:23](=O)[O:22]C(C)(C)[O:20]2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]([OH:20])[C:23]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:22])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)C=C1OC(C)(C)OC1=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Product: CN(C(=O)C=C(O)C(=O)NS(C)(=O)=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Yield: 72.2 %

Procedure:
Reaction of N-[1-(4-chlorobenzyl)-2-(4-chlorophenyl)-ethyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (0.363 g, 0.81 mmol) with methanesulfonamide (0.077 g, 0.81 mmol) as described in the preparation of compound 22 gave 0.284 g (72% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.5-3.5 (10H, m, CH3 and CH2), 4.55 and 5.1 (1H, broad m, CH), 5.8 (1H, s, CH), 7.1-7.4 (8H, m, aromatics).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(C(F)(F)F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>C(O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:4]3[N:3]=[C:2]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([NH2:30])=[CH:24][CH:25]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Reactant: Nc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4ccc(N)cc4)nn23)cc1
Yield: 84.5 %

Procedure:
1.0 g 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) and 2.7 g p-phenylene-diamine are stirred at 170° C. for 5 h. The reaction mixture is diluted with 6 ml ethanol and the precipitate is filtered with suction. The solid is recrystallized from N,N-dimethylformamide to yield 1.04 g of the title compound (m.p.: 295° C.).
Reaction SMILES: O.[CH:2]1[C:14]2[CH:13]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:26]([NH:28][C:29]3[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=3[C:31]([OH:33])=O)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[CH:11]1[C:12]2[CH:13]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:26]3[O:27][C:31](=[O:33])[C:30]4[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:29]=4[N:28]=3)[CH:23]([CH3:24])[CH3:25])=[O:20])=[O:16])[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(NC(=O)[C@@H](NC(=O)CNC(=O)C2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2nc([C@@H](NC(=O)CNC(=O)C3c4ccccc4-c4ccccc43)C(C)C)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
33 mg of water-soluble carbodiimide hydrochloride was added under ice-cooling to a solution of 72 mg of 2-[[[N-(9-fluorenylcarbonyl)glycyl]-L-valyl]amino]-6-methylbenzoic acid in 3 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for 0.5 hour and, then, at room temperature for 18 hours. The mixture was concentrated to give a residue which was purified by a silica gel column chromatography (eluting solution: methylene chlorideether) to afford 60 mg of 2-[1(S)-[[N-(9-fluorenylcarbonyl)glycyl]amino]-2-methylpropyl]-5-methyl-4H-3,1-benzoxazin-4-one as a white powder (see Table 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C4CCCCO4)[CH:28]=3)[CH:23]=2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=3)[CH:21]=[N:20][CH:19]=2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Fc1ccccc1-c1cc(-c2cncc(-c3cnn(CCOC4CCCCO4)c3)c2)c2cccnc2n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: OCCn1cc(-c2cncc(-c3cc(-c4ccccc4F)nc4ncccc34)c2)cn1
Reaction time: 1 h

Procedure:
A solution of 219 mg (0.44 mmol) 2-(2-fluoro-phenyl)-4-(5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyridin-3-yl)-[1,8]naphthyridine in 7 ml dichloromethane was treated with 0.52 ml of a 4 N solution of hydrochloric acid in dioxane. The reaction mixture was stirred for 60 minutes and the precipitate that had formed was filtered off. The residue was dissolved in water and treated with saturated sodium carbonate solution. The resulting precipitate was filtered off, washed with water and dried under vacuum yielding 2-(4-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-3-yl}-pyrazol-1-yl)-ethanol as colorless crystals; HPLC-MS: 1.70 min, [M+H] 412.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([O:18][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H]1OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 85.3 %

Procedure:
A mixture of (2R,3S)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid (1.07 g, 4.25 mmol) (The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004), (bromomethyl)benzene (0.87 g, 5.1 mmol) and potassium carbonate (1.16 g, 8.5 mmol) in acetonitrile (20 mL) was stirred at 65° C. for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=4/1) to give the title compound as colorless oil (1.23 g, 85%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37]([OH:41])([C:39]#[CH:40])[CH3:38])=[CH:33][CH:32]=1>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#CC(C)(O)c1ccncc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccncc3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-4-yl)but-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(pyridin-4-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 8.80 (d, J=5 Hz, 2H), 8.27 (d, J=5H, 2H), 7.80 (d, J=8 Hz, 1H), 7.71 (s, 1H), 7.56 (m, 3H), 7.48 (d, J=8 Hz, 1H), 7.34 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.83 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2. found: 528.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([F:21])[CH:23]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Nc1cccc(F)c1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(F)c2)C1
Yield: 33.2 %

Procedure:
The title compound (D116) (40 mg) was prepared according to the experimental procedure described in Description 115 starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (120 mg, 0.374 mmol) and 3-Fluoroaniline (0.036 ml, 0.374 mmole).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:26][CH:25]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Yield: 43.1 %

Procedure:
A solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.134 g, 0.48 mmol), 4-(4-isopropyl-piperazin-1-yl)-phenylamine (0.118 g, 0.54 mmol) and diisopropylethylamine (0.093 mL, 0.54 mmol) is stirred at 90° C. for 18 hours. The reaction mixture is concentrated in vacuo and partitioned between DCM and sat. NaHCO3. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 98:2 DCM:MeOH to afford the title compound (0.086 g, 43%).
Reaction SMILES: [CH3:1][C:2](=[CH:14][CH:15]=[CH:16][C:17]([CH3:21])(O)[CH:18]=[CH2:19])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13].[BrH:22].O>CCOCC>[CH3:1][C:2](=[CH:14][CH:15]=[CH:16][C:17]([CH3:21])=[CH:18][CH2:19][Br:22])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13]
Reactant: C=CC(C)(O)C=CC=C(C)C#CC1=C(C)CCCC1(C)C
Reactant: Br
Solvent: CCOCC
Solvent: O
Product: CC(C#CC1=C(C)CCCC1(C)C)=CC=CC(C)=CCBr
Reaction time: 0.25 h

Procedure:
2.84 g of the alcohol III prepared as described in Example 1 were dissolved in 50 ml of ether and an equimolar amount of a solution of HBr in ether was added dropwise at -70° C., whilst stirring. The reaction mixture was then kept for 15 minutes at from -60° to -70° C. and thereafter for 15 minutes at -15° C. 30 ml of water were then added and the organic phase was separated off, washed neutral, dried and concentrated. 3.2 g of a residue (crude yield 93.5%) were left; the structure of the material was determined by IR, NMR and UV spectroscopy.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:12][OH:13])([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]=O>Cl>[C:9]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][O:13][CH2:14][O:1][CH2:2]1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(CO)(CO)C(C)=O
Reactant: C=O
Agent: Cl
Product: CCOC(=O)C1(C(C)=O)COCOC1
Temperature: 25 °C
Yield: 14 %

Procedure:
A solution of ethyl 2,2-bis(hydroxymethyl)-3-oxobutanoate (75 g, 0.39 mol) and 40% formaldehyde (360 mL) in concentrated hydrochloric acid (360 mL) was heated at 50° C. for 17 h. The two-phase solution was cooled to room temperature and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water, dried over magnesium sulfate, and evaporated to give a residue, which was purified by flash column chromatography eluting with a continuous gradient of petroleum ether/ethyl acetate 15:1 to 9:1 to afford the title compound (33 g, 14%, 2 steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.25 (m, 3H), 2.31 (s, 3H), 4.25-4.19 (m, 4H), 4.35 (d, J=12.0 Hz, 2H), 4.77 (d, J=6.0 Hz, 1H), 4.82 (d, J=6.0 Hz, 1H).