Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[CH3:19][C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)=[N:10][CH:9]=1
Reactant: CCOC(=O)c1nc(C)cnc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cnc(Nc2cncnc2)c(C(=O)O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
6-Methyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid ethyl ester (300 mg, 1.15 mmol) was dissolved in a THF/ethanol (5 ml/1 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (4.7 ml, 1N aqueous solution). The reaction mixture was allowed to warms to ambient temperature and stirred at that temperature for 1 hour. The pH value was subsequently adjusted to acidic and the resulting suspension was filtrated. The precipitate was washed with water and ethyl acetate and dried to yield the product as light yellow solid (185 mg, 69%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[N:3]1.Br[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH:22]([CH3:41])[N:23]([C:27]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[N:30]=[C:29]([NH2:40])[N:28]=3)[CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:41][CH:22]1[CH2:21][C:20]2[C:25](=[CH:26][C:17]([C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[CH:18][CH:19]=2)[CH2:24][N:23]1[C:27]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:30]=[C:29]([NH2:40])[N:28]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3ccn(C)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.5 mg, 0.0518 mmol), 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.018 g, 0.043 mmol) (Peak 1, Example 49, Step 7), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.916 mg, 0.00129 mmol), and sodium carbonate (9.14 mg, 0.0862 mmol) in 1,4-dioxane (0.50 mL) and water (0.10 mL) was vacuumed and refilled with N2 for 3 times and then stirred at 90° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=419.3.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][S:27]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=3)(=[O:29])=[O:28])=[C:19]([CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1

Procedure:
Using 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (0.302 g, 0.744 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.09 g, 4.61 mmol) the title compound was prepared according to the procedure in Example 1, step 9. Purification on Dynamax C18 eluting with 85% CH3CN/H2O (0.1% TFA added) gave 0.20 g (44%) of the title compound as a yellow solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.59 (s, 3 H), 2.16 (s, 6 H), 2.45 (s, 3 H), 7.19 (S, 2 H), 7.46-7.52 (m, 4 H), 7.65-7.69 (m, 1 H), 8.07 (d, 1 H), 8.21 (d, 1 H). IR (KBr) 3450, 2900, 1675, 1385 and 1185 cm-1. mass spectrum (-ESI), m/z 609/611 (M-H). Anal. Calcd. for C29H23BrO6S2.0.7H2O: C, 55.81; H, 3.94 N, 0.00. Found: C, 55.93; H, 4.23 N, 0.12.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19].O>CN(C)C=O>[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccc(C(C)C)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 5.92 g, 148 mmol) in N,N-dimethylformamide (150 ml) was added at 0° C. triethyl 2-phosphonopropionate (35.0 g, 148 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 4-isopropylbenzaldehyde (20.0 g, 135 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 30.1 g (96% yield) of the oily title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([F:31])[CH2:33][CH2:34]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: FC1CCNCC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)CC2)c1OCCC(C)c1ccc(F)cc1
Yield: 41 %

Procedure:
Example 8a (89 mg, 0.18 mmol) was reacted with 4-fluoropiperidine hydrochloride (4.0 eq.) as described under General Procedure J and the crude mixture was purified by flash chromatography (silica gel, Et2O/hexane 3:2) to afford the title compound (38 mg, 41%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.66 (m, 1H), 4.05 (t, J=5.9 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 3.83 (s, 3H), 3.00 (m, 1H), 2.64-2.59 (m, 4H), 2.50 (s, 3H), 2.44-2.36 (m, 2H), 2.18 (s, 3H), 2.05-1.97 (m, 2H), 1.94-1.81 (m, 4H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 510.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH3:17]>C1COCC1>[NH2:17][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: N
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: NC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 48.8 %

Procedure:
To 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio- 2-nitroethylene were added 45 ml of EtQH, 10 ml of THF and 1.02 g of 25% aqueous ammonia and the mixture was stirred at an external temperature of 60° C. for 5.5 hours. During this period, 1.02 g each of 25% aqueous ammonia was added after 1, 2 and 3 hours of reaction. The reaction mixture was ice-cooled and stirred, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that order, and dried. The procedure gave 1.11 g of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]C)=O)[N:3]=1.C(O)C.[CH3:14][NH2:15]>>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH:15][CH3:14])=[O:9])[N:3]=1
Reactant: COC(=O)c1n[nH]c(N)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1n[nH]c(N)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (800 mg, 5.63 mmol) and methylamine ethanol solution (30%, 10 ml) was stirred for 3 h at 80° C. The resulting mixture was concentrated under vacuum to afford 5-amino-N-methyl-1H-1,2,4-triazole-3-carboxamide as a white solid (0.5 g, 63%).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[NH:5][N:4]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[NH:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C(=O)O)[nH]n1
Yield: 53.5 %

Procedure:
To a stirred solution of ethyl 3-ethyl-1H-pyrazole-5-carboxylate (41.3 g) in methanol (300 ml) was added dropwise 10M sodium hydroxide solution (63 ml) and the mixture heated at reflux for 4 h. The mixture was allowed to cool overnight and then concentrated. The residue was diluted with water (250 ml) and washed with toluene (3×100 ml). The aqueous phase was acidified to pH=4 by the addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water and dried in a vacuum oven at 45° C. to give the title compound (18.4 g) as a buff solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]3[N:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)(O)[O-].[Na+]>>[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:7][CH2:6]1
Reactant: c1ccn2c(SCCN3CCC4(CC3)OCCO4)nnc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCN(CCSc2nnc3ccccn23)CC1
Yield: 62.4 %

Procedure:
6.5 g of 3-[2-(1,4-dioxa-8-azaspiro(4,5)decan-8-yl)ethylmercapto]-1,2,4-triazolo(4,3-a)pyridine, prepared in Example 53, are heated under reflux for 10 hours in 200 ml of a 0.5N solution of hydrochloric acid. The reaction mixture is then cooled, rendered basic with a solution of sodium bicarbonate and extracted with chloroform. The chloroform phase is dried over magnesium sulfate and concentrated in vacuo. The residue obtained crystallizes from isopropyl acetate. The crystals are filtered off and dried to give 3.5 g of 3-[2-(4-oxopiperidin-1-yl)ethylmercapto]-1,2,4-triazolo(4,3-a)pyridine in the form of crystals melting at 76°-7° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([O:26][CH3:27])[CH:18]=2)[CH2:13][CH2:12]1>CCOC(C)=O.[Pd]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([O:26][CH3:27])[CH:18]=2)[CH2:15][CH2:16]1
Reactant: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4CCF)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4CCF)CC2)ccc1N
Reaction time: 96 h
Yield: 98.3 %

Procedure:
To (1S,4S)-2-(2-fluoroethyl)-5-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2,5-diazabicyclo[2.2.1]heptane (0.22 g, 0.58 mmol) in EtOAc (10 mL) was added Pd (10%) on carbon (50 mg). The reaction was evacuated then refilled with H2 gas from a balloon. The reaction was stirred under a balloon atmosphere of H2 for 4 days. The reaction was evacuated and the atmosphere replaced with N2. The solution was filtered to remove Pd/C and rotovaped down to give the title compound of step D as a purple oil (200 mg, 0.57 mmol, 98% yield). 1H NMR (400 MHz, CDCl3) δ 6.62 (d, J=8.4 Hz, 1H), 6.51 (d, J=2.6 Hz, 1H), 6.41 (dd, J=8.4, 2.6 Hz, 1H), 4.62-4.39 (m, 2H), 3.82 (s, 3H), 3.57 (br s, 1H), 3.47-3.38 (m, 2H), 3.35 (br s, 1H), 2.98-2.56 (m, 8H), 2.46-2.39 (m, 1H), 1.97-1.53 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[S:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[O:30][CH3:31])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:30][CH3:31])=[C:21]([CH:26]=1)[CH2:20][S:19][C:9]1[N:8]([CH2:7][C:6]([OH:32])=[O:5])[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[N:10]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(C(C)=O)cc1CSc1nc2cc(C=O)ccc2n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)=O)cc1CSc1nc2cc(C=O)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of tert-butyl[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-formyl-benzoimidazol-1-yl]-acetate (Precursor 5-HCO—H-11b, 16 mg, 0.035 mmol) in TFA/dichloromethane (1:1, 4 ml) is allowed to stir overnight at rt. The solvents are removed under a stream of air and the resulting products are dried under high vacuum. This yields the title compound (14 mg) in 100% as a yellow solid: tR=0.94 min (LC-3), ESI-MS (pos.): m/z 398.86 [M+H]+, ESI-MS (neg.): m/z 397.06 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.46 (s, 3H, COCH3), 3.88 (s, 3H, OCH3), 4.59 (s, 2H, SCH2), 4.96 (s, 2H, CH2CO2), 7.11 (d, 1Harom), 7.65 (d, 1Harom), 7.74 (d, 1Harom), 7.90 (dd, 1Harom), 8.06 (d, 1Harom), 8.12 (d, 1Harom), 10.01 (s, 1H, CHO).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[C:28]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:42])([O:30][CH2:31][CH3:32])=[O:29].COC1C=CC(C=O)=CC=1>C(O)C>[OH:42][C@@H:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:41][C@@H:33]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C1Cc2ccccc2C1=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1Cc2ccccc2[C@H]1O
Reaction time: 48 h
Yield: 84.2 %

Procedure:
Colletotrichum gloeosporioides is cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H2O (0.5 gram), NaNO3 (2 grams), FeSO4.7H2O (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of 2-carboethoxy-1-indanone is dissolved in 2 ml of 95% ethanol the resulting solution is added to the culture, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.7 grams of (1S,2S)-1-hydroxy-2-carboethoxyindane as a yellow oil. The chiral purity of the product is greater than 98% as judged by chiral chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 46.2 %

Procedure:
Piperidine (660 μl, 6.66 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 1 ml) solution of 4-chloro-3-nitrotoluene (358 mg, 2.08 mmol, commercially available product). The resulting mixture was stirred at 100° C. for 17 hours. The mixture was cooled to room temperature, and then water was added thereto. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=50/1). Thus, 1-(4-methyl-2-nitrophenyl)piperidine (212 mg, 46.2%) was yielded as a colorless oily material. TLC Rf 0.54 (hexane/ethyl acetate=10/1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[CH:7]=[CH:8][CH3:9])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[CH:7]/[CH:8]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:9])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC=CC(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C/C(C)P(=O)(OCC)OCC)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acidethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 (12 hours) yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[S:18]1[C:22]([C:23]2[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=2)[CH:28]=O)=[CH:21][C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]1=2>C(O)C>[S:18]1[C:22]([C:23]2[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:28]=[CH:14][C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])[CH:30]=2)=[CH:21][C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]1=2
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=CC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3′,4′,5′-Trimethoxyacetophenone (1.62 g, 7.7 mmol) was dissolved in ethanol (50 mL). Sodium hydroxide solution (50%, 4 mL) was added and the mixture was stirred at room temperature for 30 minutes. 5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (2.2 g, 7.7 mmol) from Ex-6A was added, and the mixture was stirred at room temperature overnight. The resulting yellow precipitate was filtered out, rinsed with water and dried over an oil pump to give 3.4 g (92%) of the desired 3-[5-(benzo[b]thien-2-yl)-2,4-di-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one product as a solid, m.p. 194-196° C. 1H-NMR (300 MHz, CDCl3): 8.09 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.67 (s, 1H), 7.52 (d, 1H), 7.25-7.38 (m, 4H), 6.57 (s, 1H), 3.9-4.1 (m, 15H). Anal. Calculated for C28H26O6S: C, 68.55, H, 5.34, S, 6.53; found C: 68.48, H: 5.43, S: 6.52.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[F:20][CH:21]([F:25])[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[F:20][CH:21]([F:25])[C:22]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:23]
Reactant: O=C(O)C(F)F
Reactant: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nccc(I)c1-c1cc2ccc(NC(=O)C(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 2,2-difluoroacetic acid (12 mg, 0.12 mmol) and HATU (47 mg, 0.12 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2,2-difluoro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-acetamide (24 mg, 67%) as a white solid. MH+ 443.9.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C:5](=[O:13])[O:4]1.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([O:34][CH2:2][C@H:3]3[C@H:7]4[C@H:6]([O:10][C:9]([CH3:12])([CH3:11])[O:8]4)[C:5](=[O:13])[O:4]3)[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CC1(C)O[C@H]2[C@H](CBr)OC(=O)[C@H]2O1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC[C@@H]1OC(=O)[C@H]2OC(C)(C)O[C@@H]12

Procedure:
The title compound was prepared from (3aS,6R,6aR)-6-(bromomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4-(3aH)-one and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.83 (s, 2H), 7.98 (d, 1H), 7.23 (s, 1H), 5.16 (m, 2H), 4.87 (m, 1H), 4.67 (s, 1H) 4.36 (m, 2H), 3.93 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H); MS (ESI): 522.8.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C.C(O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=[N+]([O-])c1ccc2c(c1)C=NCC2
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)CC1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 120 °C

Procedure:
A suspension of 7-nitro-3,4-dihydroisoquinoline (10.0 g, 56.1 mmol) and malonic acid (11.7 g, 112 mmol) in acetic acid (55 ml) was heated at 120° C. for 0.5 h. Upon cooling, the solvent was concentrated to give a red oil which was taken up in aqueous ethanol (50 ml of 75%). After crystallization had occurred, the solvent was cooled to 0° C. and the product collected. The title compound was isolated as a tan solid (10.9 g, 81%), m.p. 264-5° C. (dec.).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and 4-chlorobenzaldehyde (1.05 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 153-155° C., 1H-NMR (CDCl3) δ: 2.42 (d, J=1.2 Hz, 3H), 4.65 (m, 2H), 5.2 (m, 2H), 6.15 (m, 1H), 6.91-7.61 (m, 8H).