Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:29])[CH3:28])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1(C)C=CC([S:39]([O-:42])(=[O:41])=[O:40])=CC=1.C(N(CC)CC)C.C([OH:53])C>O>[CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:28])[CH3:29])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.[S:39]([O:22][C:21]1[C:20](=[CH:19][CH:18]=[CH:14][CH:13]=1)[C:23]([O-:24])=[O:53])([OH:42])(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCO
Agent: C[C@H]1c2cccc(O)c2C(=O)C2=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Solvent: O
Solvent: CCN(CC)CC
Product: O=C([O-])c1ccccc1OS(=O)(=O)O

Procedure:
Doxycycline p-toluenesulphonate (40.0 g) prepared according to the process above was suspended in a mixture of ethanol (72.0 ml) and water (24.0 ml), with stirring. A solution of triethylamine (9.04 ml) in ethanol (9.04 ml) was added, causing dissolution followed by crystallisation. After stirring for 20 minutes, ethanol (144 ml) was added and the mixture stirred for a further 1 hour 30 minutes. The crystals were filtered, washed with ethanol (25 ml), then with acetone (12.5 ml) and dried at 35° C. The product, doxycycline monohydrate, weighed 22.12 g and complied with the U.S. Pharmacopoeia monograph requirements. The mother liquors were diluted with an equal volume of water and 5-sulphosalicylic acid (2.0 g) was added. After stirring overnight, the deposited solid was filtered, washed with 66% aqueous methanol and then with acetone, dried at 35° C., and gave 1.53 g of doxycycline sulphosalicylate.
Reaction SMILES: I[CH3:2].[OH-].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1)[C:16]#[N:17].Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]([C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[Cl:5])([CH3:2])[C:16]#[N:17])=[CH:19][C:20]=1[C:25]([F:28])([F:26])[F:27]
Reactant: CI
Reactant: N#CC(c1ccc(Cl)c(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C#N)(c1ccc(Cl)c(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1Cl
Yield: 87.8 %

Procedure:
To a stirred mixture of 14.2 parts of iodomethane, 153 parts of a sodium hydroxide solution 50%, 1 part of N,N,N-triethylbenzenemethanaminium chloride and 67.5 parts of tetrahydrofuran was added dropwise, during a period of 15 minutes, a solution of 37.5 parts of 2-chloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-4-nitrobenzeneacetonitrile in 67.5 parts of tetrahydrofuran. The reaction mixture was stirred and heated for 4 hours at 50°-60° C. Another portion of 2.3 parts of iodomethane was added and the whole was stirred for 1 hour at 50° C. The mixture was poured into 1000 parts of crushed ice. The whole was acidified with concentrate hydrochloric acid. The product was extracted with trichloro-methane. The extract was dried, filtered and evaporated. The residue was stirred in 160 parts of ethanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 34.2 parts (87.8%) of 4-chloro-α-(2-chloro-4-nitrophenyl)-α-methyl-3 -(trifluoromethyl)benzeneacetonitrile; mp. 162.5° C. (intermediate 17).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.[OH-].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1O
Reactant: Nc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(-c2nc3ccccc3o2)c1
Temperature: 200 °C

Procedure:
3-Aminobenzoic acid (500 mg, 3.65 mmol) and 2-aminophenol (398 mg, 3.65 mmol) were mixed with polyphosphoric acid (5 ml). The reaction was heated to 200° C. for 4 h. The reaction mixture was slowly poured into ice water (100 ml) and the resulting mixture basified with solid sodium hydroxide. At pH5–6 the precipitate was filtered, washed with water and dried to give the subtitle compound, 625 mg (82%). 1H NMR (CDCl3) δ 7.78(m, 1H), 7.65(d, J=7.5 Hz, 1H) 7.59(m, 2H), 7.36(m, 3H), 6.86(dd, J=2.2, 7.9 Hz, 1H). MS 211 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:17]([CH:18]=[O:19])[C:9]2=3)=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:17]([CH2:18][OH:19])[C:9]2=3)=[CH:4][CH:3]=1
Reactant: O=Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)CNC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCC(c2ccc(Cl)cc2)c2c1sc(N1CCOCC1)c2CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbaldehyde (52.4 mg, 0.139 mmol, single enantiomer of unknown configurate) in methanol (1.30 mL, 32.0 mmol) was added portionwise sodium borohydride (10.5 mg, 0.278 mmol). The reaction mixture was stirred at rt for 1.5 hr, then carefully quenched by the addition of an aqueous solution of 1M HCl to lower the pH to ˜3-4. The mixture was extracted w/EA twice, the extracts were combined, washed w/brine, dried over Na2SO4, filtered, and concentrated in vacuo. HPLC purification provided the title compound as a white solid (33 mg, 62%). LCMS: (FA) ES+ 379, 381. 1H NMR (400 MHz, DMSO) δ 7.41 (d, J=4.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.03-7.01 (m, 2H), 4.97 (t, J=4.9 Hz, 1H), 4.36 (d, J=4.5 Hz, 1H), 4.19 (dd, J=11.9, 5.4 Hz, 1H), 3.91-3.82 (m, 2H), 3.78-3.66 (m, 4H), 3.31-3.25 (m, 1H), 3.20-3.12 (m, 2H), 3.00-2.92 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)Cc2ccc(C)nc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(NCCc2ccc(C)nc2)cc1
Temperature: 0 °C
Yield: 28.1 %

Procedure:
2-(6-Methyl-pyridin-3-yl)-N-p-tolyl-acetamide (0.960 g, 4 mmol) was dissolved in dry THF (20 cm3), and cooled to 0° C. LiAlH4 (5.0 eq., 20 mmol, 10 ml of a 2.0 M solution in THF) was added dropwise at first, until no more gas evolution was observed (˜0.5 ml), and then the remaining LiAlH4 solution was added in one portion. The resulting solution was heated to reflux for 16 hours with stirring. Wet diethyl ether was then added until no further gas evolution was observed, the resulting medium filtered, and the residue washed with ether (˜50 cm3). The filtrate was dried (MgSO4), and the solvent removed to yield a crude yellow oil. The oil was purified by flash chromatography, eluting with 1:1 petrol (40-60)/EtOAc. The product was collected as the fraction with Rf=0.294. The product was obtained as a pale yellow oil (254 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Br)cn1
Reaction time: 0.5 h

Procedure:
The commercially available 5-bromopyridine-2-carbaldehyde (2.0 g, 10.8 mmol) was dissolved in methanol (60 mL) and solid sodium borohydride (407 mg, 10.8 mmol) was added at 20° C. The reaction was stirred 30 minutes then the solvent was removed and 25 mL of saturated ammonium chloride solution was added and the reaction was extracted with 200 mL EtOAc which was washed with water and brine, 30 mL each. The organic phase was dried over magnesium sulfate and filtered through a 2 cm silica gel pad. The clear filtrate was concentrated by rotary evaporation to give a white solid, 1.99 g which was used as is.
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:4])[CH3:3].[C:27](Cl)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:8]2[O:7][C@@H:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:9]2)=[CH:13][CH:14]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)N1CC(COc2ccc(CCO)cc2)O[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc(OCC2CN(C(C)(C)C)[C@H](c3ccccc3)O2)cc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
The residue from Example 1, Step A (2.55 g, 6.3 mmol) was dissolved in pyridine (10 ml), cooled to -15° C. and acetyl chloride (547 mg, 6.9 mmol) was added. The mixture was stirred at 0° C. for 3 hours then at room temperature overnight. The solvent was removed in vacuo. To the residue, dil. Na2CO3 solution was added (30 ml) and the mixture was extracted with CHCl3 (50 ml then 20 ml). The combined CHCl3 extracts were washed with H2O (30 ml), dried over Na2SO4 and evaporated in vacuo. The residue was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[CH3:29])[CH:7]=1)[CH3:2].I[CH2:32][CH3:33]>>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[CH3:29])[CH:7]=1)[CH2:32][CH3:33])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Reactant: CCI
Product: CCOC(=O)C(CC)c1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 108, step 1, using the following starting materials: [3-(6-Chloro-2-methyl-1-pyridin-3-yl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and iodoethane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12](I)[N:11]=2)[CH:9]=1)[CH3:2].[O:19]=[C:20]1[C@@:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH2:26][C:27]#[CH:28])[CH2:24][CH2:23][CH2:22][N:21]1[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42].N(CC)CC>C1COCC1.CCOC(C)=O.CCCC(C)C.[Cu](I)I>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:28]#[C:27][CH2:26][C@@:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24][CH2:23][CH2:22][N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[C:20]3=[O:19])[N:11]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(I)n2)c1
Reactant: C#CC[C@@]1(NC(=O)OC(C)(C)C)CCCN(COCC[Si](C)(C)C)C1=O
Agent: I[Cu]I
Solvent: CCCC(C)C
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(NC(=O)OC(C)(C)C)CCCN(COCC[Si](C)(C)C)C3=O)n2)c1
Temperature: 20 °C
Reaction time: 90 h
Yield: 71.2 %

Procedure:
Copper iodide (17.27 mg, 0.09 mmol), followed by PdCl2(Ph3P)2 (31.83 mg, 0.05 mmol) was added portionwise to a solution of 4-(5-ethoxy-2-fluoro-phenyl)-2-iodo-6-methyl-pyrimidine (which may be prepared as described in Description 17) (389.81 mg, 1.09 mmol), tert-butyl N-[(3S)-2-oxo-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)-3-piperidyl]carbamate (which may be prepared as described in D25) (347 mg, 0.9100 mmol) and Et2NH (0.47 mL, 4.54 mmol) in THF (10 mL) under N2 and the reaction was stirred at 20° C. for 90 hrs. The solvent was evaporated and the residue was purified using a Biotage SP4 with a 25 g SNAP cartridge, eluting with 0 to 50% EtOAc/i-hexane affording the tert-butyl N-[(3S)-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-2-oxo-1-(2-trimethylsilylethoxymethyl)-3-piperidyl]carbamate (D26) (397 mg, 0.6478 mmol, 71.4% yield) as a dark yellow oil.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:66](O)(=[O:69])[CH2:67][OH:68]>CN(C=O)C>[OH:69][CH2:66][C:67]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:68]
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CO)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in DMF (5 mL). N-Ethyldiisopropylamine (0.081 mL, 0.47 mmol) was added followed by O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and glycolic acid (0.025 mL, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude dissolved in DMF and acetonitrile, filtered and purified by prep. HPLC. The fractions containing the title compound were pulled together and freezed-dried over the weekend yielding 2-hydroxy-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (21.0 mg, 18.49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[C:4]([N+:20]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:20][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=1)(=[O:9])=[O:10]
Reactant: CSc1cccc(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CSc1cccc(NS(=O)(=O)c2ccc(F)cc2N)c1
Yield: 98.8 %

Procedure:
The title compound (780 mg, 2.50 mmol) was prepared from 4-fluoro-N-[3-(methylsulfanyl)phenyl]-2-nitrobenzenesulfonamide (865 mg, 2.53 mmol) and SnCl2 (1.44 g, 7.59 mmol) using the methods of (IntA1), Step 2.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]1[CH2:12][S:9](=[O:11])(=[O:10])[O:8][CH2:7]1.C1COCC1>C(#N)C>[CH:1]1([NH:5][CH2:7][CH2:6][CH2:12][S:9]([OH:11])(=[O:10])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCNC1CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A mixture of cyclobutylamine (1.11 g, 15.6 mmol) and 1,3-propane sultone (2 g, 17 mmol) in acetonitrile (18 mL) was heated at reflux. The mixture turned to a lump within 15 minutes. THF (10 mL) was added. The reflux was maintained for 1 hour. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with acetonitrile (2×4 mL), air-dried for 60 minutes (2.41 g). The solid was suspended in methanol (20 mL) and the suspension was heated at reflux until all the solid material was dissolved. The mixture was then cooled to room temperature. The solid thus formed was collected by suction filtration, rinsed with methanol (2×4 mL), air-dried for 20 minutes, and further dried in a vacuum oven at 40° C. for 18 hours. Compound EC was obtained as a white solid (1.81 g, 60% yield). 1H NMR (500 MHz, D2O) δ 1.70-1.77 (m, 2H), 1.94-2.03 (m, 4H), 2.18 (br s, 2H), 2.85 (t, J=6.8 Hz, 1H), 2.95 (t, J=7.3 Hz, 1H), 3.63-3.66 (m, 1H). 13C NMR (125 MHz, D2O) δ 14.5, 21.5, 26.1, 43.6, 48.0, 51.8. ES-MS 194 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.ClCCCl.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
Into a mixture of 1.0 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one, 42 μl of boron trifluoride-diethyl ether complex and 40 ml of 1,2-dichloroethane, 0.4 ml of ethyl diazoacetate (purity: 90%) was dropped at room temperature over 2 hours. After dropping, the reaction mixture was further stirred for two hours, and then subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give 1.10 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(ethoxycarbonylmethoxy)pyridine:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C.CC(C)=O>[CH3:17][O:16][C:3]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[CH:15][C:6]2[C:7]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)cc(C(C)C)c2cc1O
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: COc1cc2oc(=O)cc(C(C)C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 85 %

Procedure:
Method D (2.5 h at 85° C.); starting materials: 6-hydroxy-7-methoxy-4-(1-methylethyl)-2H-1-benzopyran-2-one (example 105) and 1-(3-chloropropyl)-4-phenyl-piperidine; yield 85%; fusion point 62°-65° C. (from TBME). Fumarate: method E; yield 65%; fusion point 155°-157° C. (from acetone, boiled out with TBME).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](OCC)=[O:27])=[CH:20][CH:19]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:22][CH:23]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: OC/C=C/c1ccc(-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The colourless gum (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-prop-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(3′,5′-dichloro-biphenyl-4-yl)-acrylate as described for example 52b.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH2:39][CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH2:39][CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CCO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CCO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3c(C)noc3C)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in analogy to example 62 using 3,5-dimethyl-isoxazole-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-ethoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 526.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)=[CH:45][CH:46]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: Cn1ncc(COc2ccc(CO)cc2)c1-c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(N(Cc2ccc(OCc3cnn(C)c3-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (182 mg, 0.5 mmol), (4-{[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]methoxy}phenyl)methanol (156 mg, 0.5 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in dichloromethane (5 mL) was added diethyl azodicarboxylate (40% toluene solution, 435 mg, 1.0 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give a yellow oil containing the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:39][C:40]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:41]=1[C:42]([NH2:44])=[O:43]>CC(N(C)C)=O>[CH3:52][O:51][C:45]1[CH:46]=[C:47]([O:49][CH3:50])[CH:48]=[C:40]2[C:41]=1[C:42](=[O:43])[NH:44][C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH:18]([CH3:19])[CH3:20])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]3)=[CH:21][CH:22]=1)=[N:39]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N(C(C)C)C1CCN(Cc2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCC(N(C(C)=O)C(C)C)CC4)cc3)nc2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
A mixture of N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide (0.770 g, 2.5 mmol), NaHSO3 (0.350 g, 3.3 mmol), and p-TsOH (0.100 g, 0.51 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.500 g, 2.5 mmol) in DMA (20 mL). The reaction was stirred at 130° C. for 5 hours and concentrated in vacuo. The residue was diluted with H2O and saturated NaHCO3, then extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, afforded the title compound (0.670 g, 56%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.13 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (d, J=1.9 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 3.85-3.95 (m, 7H), 3.43-3.71 (m, 3H), 2.55-3.00 (m, 3H), 1.97-2.09 (m, 5H), 1.70-1.77 (m, 1H), 1.58-1.61 (m, 1H), 1.25-1.30 (m, 4H), 1.11-1.13 (m, 3H). ESI MS m/z 479 [M+H]+.