Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 9.7 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.30 g, Example 33), 4-bromophenylsulfonic acid amide (0.26 g), ethanol (6 ml), 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 90° C. for 6 hours. After work-up, the residue was purified by column chromatography on silica gel eluting with 5:95 methanol:ethyl acetate to give the title compound as a solid (0.04 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(CO)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.50 g), ammonium acetate (0.39 g) and acetic acid (4 mL) was stirred at 100° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.45 g, yield 95%) was obtained as a colorless amorphous solid from a fraction eluted with tetrahydrofuran-hexane (5:1, volume ratio). MS: 473 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=O.O.[NH2:18][NH2:19]>O1CCCC1>[F:1][C:2]([F:16])([F:15])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[N:18][NH2:19]
Reactant: O=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NN=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone (Sov. Prog. Chem. (Engl.Transi.), 1966, 32, 745, 1.8 g, 7.72 mmol) was dissolved in tetrahydrofuran (10 ml) and hydrazine monohydrate (0.56 ml, 11.58 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature then heated under reflux for 40 min. The reaction mixture was concentrated in vacui and the residue treated with water (10 ml) and extracted with dichloromethane (4×10 ml). The organic extracts were concentrated in vacuo and the residue was purified by chromatography on silica gel (100 g), eluting with diciforomethane: hexane (1:1 and then 2:1). The product was obtained as an amber gum (159 mg, 8%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]1.[CH2:15]([S:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[CH2:15]([S:19][C:20]1[N:21]=[C:22]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]2)[CH:23]=[CH:24][N:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: NC(=O)c1c[nH]c2ccccc12
Reactant: CCCCSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1nccc(-n2cc(C(N)=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
NaH (480 mg, 12 mmol, 60% suspension) was added to a solution of 1H-indole-3-carboxylic acid amide (1.6 g, 10 mmol) in DMF (5 mL) at 0° C. and stirred for 20 min. A solution of 2-butylsulfanyl-4-chloro-pyrimidine (2.23 g) in DMF (5 mL) was added at 0° C., and the mixture allowed to warm to RT overnight. Water was added to the mixture, and the resulting white solid filtered off, washed with water (20 mL) and DCM (20 mL) and air-dried overnight to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indole-3-carboxylic acid amide (3.224 g, 98.77% yield) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[C:5]2[C:17]([CH2:23][CH3:24])=[CH:18][C:19]([CH2:21][CH3:22])=[CH:20][C:4]=2[N:3]=1.[C:25](OCC)(=[O:28])[C:26]#[CH:27]>C(O)C>[CH2:23]([C:17]1[C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=3)=[N:7][CH2:8][C:2]3[N:3]([CH:27]=[CH:26][C:25](=[O:28])[N:1]=3)[C:4]=2[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=1)[CH3:24]
Reactant: CCc1cccc(C2=NCC(N)=Nc3cc(CC)cc(CC)c32)c1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCc1cccc(C2=NCc3nc(=O)ccn3-c3cc(CC)cc(CC)c32)c1

Procedure:
In the manner given in Example 1, 2-amino-6,8-diethyl-5-(m-ethylphenyl)-3H-1,4-benzodiazepine, ethyl propiolate and ethanol were refluxed. The mixture was chromatographed to give 8,10-diethyl-7-(m-ethylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1.O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)=[O:37])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2[nH]ncc12
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)n2ncc3c(NC(=O)N[C@@H]4CCc5cc(C(C)(C)C)ccc54)cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from Example 56J (240 mg, 0.69 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (45 mg, 1.13 mmol) and stirred at room temperature for 15 min. 4-methylpiperazine carbonyl chloride (1.64 mmol) was then added, and the reaction mixture was stirred overnight at 80° C. It was then cooled to room temperature and poured into H2O, and the resulting precipitate was collected by filtration. Chromatography on silica gel (eluted with 97:3 CH2Cl2-methanol) afforded the desired product. 1H NMR (d6-DMSO) 67 8.59 (s, 1H), 8.07 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.28 (m, 3H), 7.17 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H), 5.17 (m, 1H), 4.44 (m, 2H), 3.48 (m, 2H), 3.02 (m, 1H), 2.90 (m, 1H), 2.81 (m, 1H), 2.53 (s, 3H), 2.42 (m, 1H), 1.80 (m, 1H), 1.27 (s, 9H). MS (DCI) m/z 475 (M+H). C27H34N6O2.0.5H2O: C, 67.06; H, 7.29; N, 17.38. Found: C, 66.87; H, 7.22; N, 17.04.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:24][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]([F:6])([F:25])[F:26])=[N:9][N:10]=3)[N:13]=2)[CH2:18][CH2:19]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reaction time: 0.33 h
Yield: 60.4 %

Procedure:
Methanesulfonyl chloride (2.83 mL, 36.51 mmol) in DCM (30 mL) was added dropwise to a stirred partial solution of [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methanol (10 g, 33.19 mmol) and triethylamine (5.09 mL, 36.51 mmol) in DCM (140 mL). The reaction was stirred for 20 minutes, quenched with water (100 mL) and extracted with DCM (2×75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a yellow solid. The crude solid was triturated with ether to give a solid which was collected by filtration and dried under vacuum to give 6-[4-(methanesulfonyloxymethyl)piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (7.60 g, 60.4%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].O([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N+:33]([O-:44])=[CH:32][N:31]=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:19]([NH:18][C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=3)[N+:33]([O-:44])=[CH:32][N:31]=2)[C:3]1=[O:22])(=[O:21])[CH3:20]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: [O-][n+]1cnc(Oc2ccccc2)c2cc(C(F)(F)F)ccc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2nc[n+]([O-])c3ccc(C(F)(F)F)cc23)C1=O
Temperature: 120 °C
Yield: 110.5 %

Procedure:
Example 5, Alternative Preparation, Step 3: To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (50 mg, 0.161 mmol; see Example 1, Step 10) and 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (99 mg, 0.161 mmol) in i-PrOH (2 ml) was added N,N-diisopropylethylamine (0.056 ml, 0.322 mmol). The vessel was sealed under argon and heated in a microwave for 1 hr at 120° C. LC/MS found: (M+H)+=523.3 as the major product peak. The mixture was concentrated and purified by automated flash chromatography (40 g silica gel, eluting with 8:92 10% cNH4OH/MeOH). The fractions containing the desired product were pooled and concentrated in vacuo. The residue was crystallized from CH2Cl2 and hexane. The two crops were combined and dried under vacuum to afford the title compound, 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (93 mg). Analysis by 1H-NMR showed that this material contained ˜0.75 molar equivalents of CH2Cl2. 1H-NMR (400 MHz, d4-MeOH): δ 8.99 (s, 1H), 8.81 (s, 1H), 8.62 (d, J=8.9 Hz, 1H), 8.32 (dd, J=9.0, 1.5 Hz, 1H), 5.28 (t, J=8.4 Hz, 1H), 4.59 (br s, 1H), 4.05 (m, 1H), 3.55-3.65 (m, 2H), 3.43 (m, 1H), 2.75 (br s, 1H), 2.55 (m, 1H), 2.27 (s, 3H), 2.1-2.3 (m, 3H), 2.02 (s, 3H), 2.0 (m, 1H), 1.65-1.7 (m, 3H), 1.12 (d, J=6.0 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H). LC/MS found: [M+H]+=523.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12](O)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[N:11]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(OC)c(F)c3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 73.2 %

Procedure:
A solution of 3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 4.01 mmol) in POCl3 (5.61 ml, 60.1 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum to give 1-chloro-3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinoline (933 mg, 95% yield). δ ppm 1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=9.3 Hz, 1H), 7.90-7.87 (m, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.27-7.23 (m, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.10-7.04 (m, 1H), 3.98 (d, J=6.0 Hz, 6H); MS: MS m/z 318.1 (M++1).
Reaction SMILES: [Na].Cl[C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:4]=1.[O-:25][CH2:26][CH2:27][CH2:28][CH3:29].[Na+]>C(O)CCC>[CH2:26]([O:25][C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:4]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CCCC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium metal was added to dry butanol (5 mL, 54.6 mmol) at 0° C. then the reaction was raised to room temperature. Then, the next day, a solid precipitated. Stir N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (100 mg, 0.302 mmol) in dry butanol (5 mL). Add the previously made sodium butoxide (58 mg, 0.605 mmol) at 0° C. then raise to room temperature. After stirring overnight, the majority of the reaction was converted to product. Deamination was observed where the amide bond of the compound was cleaved. The compound was filtered and purified by preparatory HPLC 40-50% (MeCN/H2O gradient+0.01% TFA). Received 29.1 mg of a white solid (26%). 1H NMR (DMSO-d6) δ: 11.08 (s, 2H), 8.09 (d, J=2.3 Hz, 2H), 8.01 (d, J=8.6 Hz, 4H), 7.61 (d, J=8.6 Hz, 4H), 7.54 (s, 2H), 6.40 (d, J=2.0 Hz, 2H), 5.19 (s, 2H), 4.46 (t, J=6.4 Hz, 4H), 1.79-1.98 (m, 4H), 1.49-1.62 (m, 4H), 1.46 (s, 12H), 0.99 (t, J=7.5 Hz, 3H). ESI-MS: m/z 369.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH:27][CH3:28])(=[O:26])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH:27][CH3:28])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[N:7]=1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cc1ccc(Nc2nccc(-c3ccccc3OC)n2)cc1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.883 g, 0.004 mol), and C-(4-amino-phenyl)-N-methyl-methanesulfonamide (0.801 g, 0.004 mol) (Macor, John E.; Blank et al., Tetrahedron Letters (1992), 33(52), 8011-14) in DMF is stirred in DMF (12 ml) for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to give C-{4-[4-(2-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-N-methyl-methanesulfonamide.
Reaction SMILES: [C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19](O)[CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1>O>[C:1]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCCCC

Procedure:
A reaction mixture of 1 mole of palmitate acid and 3 moles of n-butanol is transferred into a reaction flask. The reaction flask is equipped with a modified Dean and Stark distillation set-up, magnetic stirrer, condenser, dropping funnel and heating plate. 1 mole of toluene is added to the reaction mixture. 40 weight percent of acidic ion exchange resin (based on weight of acidic ion exchange resin/weight of palm fatty acid used) is added to the reaction mixture when it has reached the temperature 120° C. Concentration of active sites for the acidic ion exchange resins used is not less than 1.7 equivalents per litre or not less than 4.7 equivalents per kilogram. Heating continued for not more than 5 hours. Water formed as by-product of the esterification reaction is removed continuously by means of distillation with the aid of toluene while toluene is recycled continuously back to the reaction mixture.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]([F:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][O:36][C:35]2=[O:44])[CH2:30][CH2:29]1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:23]([F:24])=[CH:22][C:18]([C:19]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[CH2:37][O:36][C:35]4=[O:44])[CH2:32][CH2:33]3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1

Procedure:
4-(N-t-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoic acid from step 6 above and 1-(4-piperidinyl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride from step 3 of Example 1 were coupled using the procedure given in step 6 of Example 1. 1-(1-(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxy-benzoyl) piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one was obtained as an amorphous solid (TLC Rf = 0.17 (4:1 EtOAc:hexanes); HPLC (method A) retention time= 9.8 min); FAB MS m/z 584 (M+ +H)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of 4-bromo-1-hexylbenzene (500 mg, 1.7 mmol) in THF (15 mL) at −78° C. was added t-butyllithium (1.7 M in pentane, 2.0 mL) slowly dropwise. After stirring at −78° C. for 1 h, trimethyl borate (0.39 mL, 3.46 mmol) was added. The reaction mixture was warmed at RT over 2 h. After stirring at RT for 15 min, the reaction mixture was quenched with saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with HCl (10% solution), brine, and dried (MgSO4), filtered, and concentrated under reduce pressure to give 415 mg (4-hexylphenyl)boronic acid as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH:17]=[O:18])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1COCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH2:17][OH:18])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc(C=O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1nc(CO)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a cooled (−78° C.) colorless solution of 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (19.9 mg; 0.044 mmol) in anhydrous toluene (2 ml) was added dropwise 1M DIBAL in THF (88 μl; 2 eq.). The resulting yellow homogeneous solution was further stirred at −78° C. for 10 min., and then at rt for 1 h. The resulting crude mixture was purified by preparative HPLC to give the pure product 3-ethyl-1-hydroxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (16 mg; 0.035 mmol; 80%). LC-MS: tR=0.91 min.; [M+H]+=454.27 g/mol.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][CH:31]([OH:33])[CH3:32])[C:5]=3[C:6]=2[CH:7]=1
Reactant: C[C@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1CC(C)O)CC2
Reaction time: 0.5 h

Procedure:
A solution of 3 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-tetralone and 150 mg of p-toluenesulfonic acid in 130 ml in anhydrous toluene was heated on a water separator. A solution of 4.16 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 3.0 g (84%) of (S)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[O:15]=[C:12]1[N:11]=[C:10]([NH:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5])[CH2:14][S:13]1
Reactant: O=C1NC(=S)CS1
Reactant: NC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@H](CO)NC1=NC(=O)SC1
Yield: 75.4 %

Procedure:
To a solution of L-serinamide hydrochloride (1.00 g) in ethanol (20 mL) were added 4-thioxo-1,3-thiazolidin-2-one (957 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.88 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (1.09 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C#CCNC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-methylprop-2-ynylamine according to conditions described in general procedure C. Mp: 97-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.88 (s, 3 H), 3.26-3.33 (m, 5H), 3.77 (t, J=4.8 Hz, 4H), 4.24 (s, 2H), 6.32 (d, J=5.5 Hz, 1H), 7.06 (d, J=14.3 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.45-7.64 (m, 5H), 7.85-7.87 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 10.49 (s, 1H).