Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C([Si](C)(C)[O:37][CH:38]([C:40]#[C:41]B1OC(C)(C)C(C)(C)O1)[CH3:39])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:41]#[C:40][CH:38]([OH:37])[CH3:39])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: CC(C#CB1OC(C)(C)C(C)(C)O1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 120 °C
Yield: 23.6 %

Procedure:
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (102 mg, 0.18 mmol, Example 69), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-yn-2-yloxy)silane (86 mg, 0.28 mmol, Combi-Blocks, San Diego, Calif.), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichloromethane complex (15 mg, 0.02 mmol, Sigma-Aldrich, St. Louis, Mo.), and cesium carbonate (180 mg, 0.55 mmol) were combined in DME (1.2 mL) and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 15 min and at 120° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na2SO4), filtered, and concentrated. The crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-2-ol (23 mg) as an off-white solid and a mixture of two enantiomers.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.O[N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45]>CN(C=O)C>[O:45]=[C:40]1[CH2:41][CH2:42][C:43](=[O:44])[N:39]1[O:3][C:2](=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[CH:11]([NH:12][C:13](=[O:14])[NH:15]2)[CH2:10][S:9]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
The method for synthesis of 2 was modified from that of Bayer and Wilchek. In brief, biotin (1; 0.31 g, 1.26 mmol) was completely dissolved in DMF (9 mL) with gentle warming. After cooling the 1 solution to room temperature without reprecipitation, it was added to N,N′-dicyclohexylcarbodiimide (DCC; 0.26 g, 1.28 mmol) and pyridine (0.10 mL, 1.26 mmol) while stirring for 5 min at room temperature, followed by the addition of N-hydroxysuccinimide (NHS; 0.19 g, 1.65 mmol) with continuous stirring for 24 h. The reaction product was filtered and concentrated under reduced pressure. The obtained solid was redissolved in 2-propanol (50 mL) with gentle heating, cooled down to room temperature, and reprecipitated at 4° C. overnight. The product was scraped out of the glassware, washed with cold 2-propanol, and air dried to give 2 as white solid (0.36 g; 82.4%). 1H NMR (400 MHz) (DMSO) δ: 6.46 (s, 1H, CONH), 6.39 (s, 1H, CONH), 4.31 (t, 1H, CHN), 4.16 (t, 1H, CHN), 3.12 (dd, 1H, CHS), 2.83 (s, 4H, CH2 of NHS), 2.71 (d, 1H, CHHS), 2.69 (t, 2H, CH2CO), 2.59 (d, 1H, CHHS), 1.43-1.68 (m, 6H). 13C NMR (100.67 MHz) (DMSO) δ: 170.42, 162.85, 61.01, 59.28, 55.33, 30.08, 27.91, 27.68, 25.51. HRMS (ESI) calculated for C14H19N3O5S, [M+Na]+ 364.0943 (calcd.), 364.0940 (found).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[CH3:35][Sn](C)(C)C>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.C1(C)C=CC=CC=1>[CH3:35][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(C)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 32 %

Procedure:
Methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (1.00 g), tetramethyltin (0.73 g), tetrakis(triphenylphosphine)palladium (0.11 g) and toluene (50 mL) were stirred with heating under reflux under an argon atmosphere for 40 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give crystals (0.28 g, 32%) of methyl 2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 80-81° C.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[CH:8]=1)=[O:6].O>CO>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@@H:10]1[C:9]2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)=[O:26]
Reactant: COC(=O)c1ccc2c(c1)[C@@H](NC(=O)c1ccccc1Cl)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[C@@H](NC(=O)c1ccccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
LiOH (6 equiv.) was added to a suspension of (8S)-8-[(2-chloro-benzoyl)amino]-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (B-07) in methanol and water and the reaction mixture was stirred at 25° C. for 4 hours. (According to TLC control: educt still present). The reaction mixture was topped up with 1 equiv. of LiOH and stirred at 25° C. for 1 hour. Methanol was distilled off and the aqueous residue was diluted with ether and dist. water. The phases were separated and the aqueous phase was acidified with 1N HCl. Finally, the aqueous phase was extracted 4× with ethyl acetate (spot test) and the extract was dried over sodium sulfate and concentrated. Yield: 84.8%
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 10.2 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:30][CH:29]=2)[N:32]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as brown solid. MS (ESI): m/z=472.6 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]1=[O:40])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]1=[O:40])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Reaction time: 2 h
Yield: 93.7 %

Procedure:
3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (2.5 g, 4.63 mmol) was added to 100 mL of a stirring solution of 15% TFA/methylene chloride in one portion. After stirring 2 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (1-10% methanol/methylene chloride) gave 1.91 g (94%) of the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:28][C:29]#[N:30])[CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg (0.26 mmol) of 5-chloro-N-[1,3-dioxo-2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-4-yl]-2-thiophenecarboxamide, 0.022 ml (0.31 mmol) of α-bromoacetonitrile and 0.072 ml (0.51 mmol) of triethylamine in 2.5 ml of DMF are stirred at room temperature overnight. The mixture is concentrated and the residue is taken up in dichloromethane, washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The product is crystallized with ether, filtered off with suction and dried under high vacuum. Alternatively, the product can be purified by chromatography on silica gel (dichloromethane/methanol mixtures).
Reaction SMILES: CN(C)[CH:3]=[CH:4][CH:5]=[O:6].P(Cl)(Cl)(Cl)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C.O1CCCC1.C1(C)C=CC=CC=1.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:24](/[CH:3]=[CH:4]/[CH:5]=[O:6])=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]=2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:18][CH:19]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1N1CCCC1
Reactant: CN(C)C=CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1c(/C=C/C=O)c(-c2ccc(F)cc2)c(-c2ccccc2)n1N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.9 g (17.9 mmol) of 90% strength 3-dimethylaminoacrolein in 30 ml of acetonitrile AR are added dropwise under nitrogen to 1.8 ml (19.2 mmol) of freshly distilled phosphorus oxychloride in 20 ml of acetonitrile AR at -5° C. The mixture is subsequently stirred for 10 minutes and 2.3 g (6.4 mmol) of the compound from Example 3 dissolved in 20 ml of acetonitrile AR and 30 ml of tetrahydrofuran AR are then added dropwise at the same temperature. The mixture is subsequently heated to reflux overnight and cooled to room temperature. The batch is added to a mixture of 4.7 g of sodium hydroxide in 300 ml of toluene/water 1:1 in such a way that the temperature does not exceed 10° C. The mixture is subsequently stirred for 10 minutes, the organic phase is separated off and the aqueous phase is extracted twice using ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulphate. After concentrating in vacuo, the residue is stirred with ethyl acetate/petroleum ether 1:1, filtered off with suction and dried in a desiccator.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([NH2:32])[N:23]=1.Cl.C(O)C>O>[NH2:32][C:24]1[N:23]=[C:22]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
19.0 mg (0.071 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water. 0.1 ml (0.1 mmol) of 1N hydrochloric acid is added, and the mixture is heated at reflux overnight. 3 ml of ethanol and a further 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added. The mixture is stirred at 100° C. for another 6 hours. The mixture is concentrated slightly and the pH is adjusted to 10 using 1N aqueous sodium hydroxide solution, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 10:1).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:40][NH:41][CH2:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:53])=[CH:45][CH:44]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:41]([CH3:40])[CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([CH3:53])=[CH:45][CH:44]=2)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Reactant: CNCc1ccc(C)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCOCC3)c2)c2ccccc12
Yield: 62 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-N-(4-methyl-naphthalen-1-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (66 mg, 62%) was prepared as a pale, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.61-8.35 (m, 2H), 8.14-8.05 (m, 2H), 7.61-7.52 (m, 3H), 7.36-7.03 (m, 3H), 5.30-5.07 (m, 2H), 4.45-4.23 (m, 2H), 3.94-3.65 (m, 6H), 3.45-3.17 (m, 4H), 3.04-2.94 (m, 4H), 2.65 (s, 3H); MS (ESI) m/e 431 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+]([C:20]1[CH:25]=[CH:24][N+:23]([O-:26])=[CH:22][CH:21]=1)([O-])=O>CN(C)C=O>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:20]2[CH:25]=[CH:24][N+:23]([O-:26])=[CH:22][CH:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OC(c2ccccc2)c2ccccc2)cc1

Procedure:
Diphenylmethanol (18.4 g, 0.1 m) was added portionwise to a suspension of sodium hydride (2.4 g, 0.1 m) in dimethylformamide (300 ml) under nitrogen. After the reaction had ceased, the suspension was treated dropwise with a solution of 4-nitropyridine-1-oxide (14 g, 0.1 m) in dimethylformamide (500 ml). This caused the colour of the mixture to change from orange to dark blue. After a further twelve hours at room temperature, the mixture was filtered and evaporated under reduced pressure, leaving a residue that crystallised from toluene giving 19.8 g of 4-[diphenylmethoxy]pyridine-1-oxide as light yellow crystals, m.pt. 155°-157° C.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][O:36][CH2:37][CH:38]=[CH2:39])[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[CH2:37]([O:36][CH2:35][C:20]1[CH:21]=[C:22]([Cl:34])[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:24][C:19]=1[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]1)[CH:38]=[CH2:39]
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (246 mg, 0.39 mmol) in THF:MeOH:H2O (2:3:1, 6 mL) was added LiOH.H2O (16.4 mg, 0.47 mmol). After being stirred for 12 h at room temperature, the reaction mixture was concentrated and the residue was dissolved in 20 mL of EtOAc. The organic layer was washed with brine and dried over Na2SO4 Concentration gave a residue, which was purified by preparative TLC (PE:EtOAc:MeOH=8:80:1, Rf=0.5) to yield 132 mg of title compound as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.42 (s, 1H), 7.11 (s, 4H), 5.93-5.87 (m, 1H), 5.24 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.11 (dd, J=1.6 Hz, 10.4 Hz, 1H), 4.85 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.51 (d, J=9.2 Hz, 1H), 4.23 (s, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.88 (d, J=12.4 Hz, 1H), 3.71-3.67 (m, 1H), 3.52-3.41 (m, 4H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); LC-MS (m/z) 463 [(M+1)+], 507 [(M+45)−].
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:15]=4[C:16](=[O:26])[C:17]=3[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:32](#[N:34])[CH3:33]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:30]=[CH:29][C:28]([NH:31][C:32](=[NH:34])[CH3:33])=[CH:27][C:15]=4[C:16](=[O:26])[C:17]=3[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC#N
Reactant: Nc1ccc2oc(-c3ccc(-n4ccnc4)cc3)c(OCc3ccccc3)c(=O)c2c1
Product: CC(=N)Nc1ccc2oc(-c3ccc(-n4ccnc4)cc3)c(OCc3ccccc3)c(=O)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
2-[(4-(imidazol-1-yl)-phenyl]-3-benzyloxy-6-amino-4H-1-benzopyran-4-one (3 g; 6.22 mmol) was suspended in acetonitrile (50 mL) and cooled at 0° C. HCl was bubbled into the solution upon saturation. The reaction was then stirred for 4 hours at r.t., upon completion, H2O (20 mL) was added and the acetonitrile removed under vacuum. The solution was then brought to pH=9 with NaOH 2N, the precipitate was filtered off and dried to give the titled compound as a bright yellow solid. Yield: 73%. TLC: (9/1 Chloroform/Methanol) Rf: 0.6.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:9][C:8]([C:10]2[C:11]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH2:39][N:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)[CH:36]=4)[C:12]=3[N:13]([CH:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=2)=[CH:7][CH:6]=1)=[N+]=[N-].O>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:13]2[C:12]3[C:32]4[C:37]([CH2:38][C:11]=3[C:10]([C:8]3[S:9][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=3)=[N:14]2)=[CH:36][C:35]([CH2:39][N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[CH:34][CH:33]=4)=[CH:25][CH:26]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CN=[N+]=[N-])s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CN)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a solution of Example 391 (7.1 g, 11.2 mmol) in tetrahydrofuran (150 mL) was added triphenylphosine (4.4 g, 16.9 mmol) and the mixture was heated to about 40° C. overnight. Water (15.2 mL) was added and heating to about 40° C. was continued for about 6 hours. The mixture was concentrated under vacuum, diluted with water, basified by addition of potassium carbonate and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1)+1% ammonium hydroxide as eluent to provide the desired product. MS (ESI): m/z 606 (M+H)+.