Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[NH:12])OCC)=[CH:3]1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>COCCOC>[ClH:1].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8](=[NH:12])[CH2:7][C:4]1[CH:5]=[CH:6][S:2][CH:3]=1
Reactant: COC(CN)OC
Reactant: CCOC(=N)Cc1ccsc1
Agent: Cl
Solvent: COCCOC
Product: COC(CNC(=N)Cc1ccsc1)OC
Temperature: 15 °C

Procedure:
A mixture of O-ethyl 3-thiopheneethanimidate hydrochloride (0.14 mol) in 1,2-dimethoxyethane (150 ml) was stirred at 15° C. 2,2-dimethoxyethanamine (0.14 mol) was added portionwise and the mixture was stirred overnight. The mixture was evaporated, yielding N-(2,2-dimethoxyethyl)-3-thiopheneethanimidamide monohydrochloride (interm. 13).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].CCN(CC)CC.CS(Cl)(=O)=O.Cl.[NH:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1)[CH3:9]
Reactant: O=C1NCCNc2ccsc21
Reactant: CC(O)c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sccc21
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 3.4 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (1.0 g, 6.39 mmol, 3.6 Eq) and Et3N (1.16 mL, 8.30 mmol, 4.7 Eq) were dissolved in anhydrous DCM (20 mL) and cooled to 0° C. under nitrogen. MsCl (645 μL, 8.30 mmol, 4.7 Eq) was added portionwise. After 3.5 hours, the reaction was poured into 1M HCl (20 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in dioxane (6 mL) and 1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (300 mg, 1.78 mmol, 1.0 Eq) was added and the reaction heated at reflux overnight. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography (ISCO™ Companion©, 40 g column, 0 to 10% MeOH/DCM) to give the title compound as an off-white solid (178 mg, 0.06 mmol, 33%); 1H NMR (DMSO D6) 1.50 (3H, d), 2.92-2.99 (1H, m), 3.13 (1H, m), 3.20-3.25 (2H, m), 5.32 (1H, dd), 6.91 (1H, d), 7.25-7.35 (2H, m), 7.36-7.41 (2H, m), 7.58 (1H, d), 7.61-7.63 (1H, m); LC/MS M+1 (obs.) 307.0.
Reaction SMILES: C(N(CC)CC)C.CS(C)=O.[C:12]([O:15][C@H:16]1[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[C@H:17]1[CH2:23][CH2:24][S:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=1)(=[O:14])[CH3:13].Cl>C(OCC)(=O)C>[C:12]([O:15][C@H:16]1[CH2:20][CH2:19][C@H:18]([CH:21]=[O:22])[C@H:17]1[CH2:23][CH2:24][S:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1csc(SCC[C@@H]2[C@@H](CO)CC[C@@H]2OC(C)=O)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Triethylamine (3.7 mL) and sulfur trioxide•pyridine complex (1.7 g) were added to a dimethyl sulfoxide (4.0 mL)/ethyl acetate (8.0 mL) solution of ethyl 2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-(hydroxymethyl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate (500 mg) (see compound 7 described in the pamphlet of International Publication No. WO 2006/129788) at 10° C., followed by stirring at room temperature for 30 min. To the reaction solution, 1 N hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (497 mg) having the following physical properties:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[N:11]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:10](=[O:33])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:34]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:15]2[CH2:16][CH2:17][C:12]3([N:11]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:10](=[O:33])[N:9]=[C:8]3[NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:13][CH2:14]2)=[CH:20][CH:21]=1)#[N:35]
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(I)cc1)CC2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(C#N)cc1)CC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-[4-(cyclohexylamino)-8-(4-iodobenzyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate (Intermediate I.3.a.1, 150 mg, 0.29 mmol), zinc cyanide (24 mg, 0.20 mmol) in DMF (3 mL) was added tetrakis (33 mg, 0.03 mmol). The resulting solution was allowed to stir at 80° C. for 16 h. After 16 h, the reaction mixture was filtered, concentrated in vacuo and purified by reverse phase preparative HPLC (5- 95% MeCN/H2O containing 0.1% TFA, C18) to provide the desired product. LRMS (M+1)=466.6.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27]>[OH-].[Na+]>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ncc(C#N)c(Oc3cccc(Br)c3)c2cc1OC
Temperature: 170 °C

Procedure:
A mixture of 0.16 g of 88% KOH and 1.73 g of 3-bromophenol at 50° C. was treated with 0.50 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile. The resulting mixture was heated to 170° C. during 30 min, cooled, and treated at 0° C. with 40 ml of 0.1N NaOH. The solid which resulted was filtered, washed with water, and dissolved in methylene chloride. The solution was washed with 0.5 N NaOH and water, dried, and concentrated. The resulting solid was recrystallized from methylene chloride-hexane to give 4-(3-bromophenoxy)-6,7-dimethoxy-3-quinolinecarbonitrile as a white solid, mp 187-190° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]4[CH:23]=[N:22][NH:21][C:20](=[O:24])[C:19]=4[Cl:25])[CH2:11][CH2:10]3)=N[O:8][C:4]=2[CH:3]=1.C[OH:29].[OH-].[Na+].[H][H]>[Pd].ClCCl>[ClH:25].[ClH:25].[F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][NH:21][C:20](=[O:24])[CH:19]=3)[CH2:11][CH2:10]2)=[O:29])=[C:4]([OH:8])[CH:3]=1
Reactant: [H][H]
Reactant: CO
Reactant: O=c1[nH]ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccc(F)cc1O)C1CCN(CCNc2cn[nH]c(=O)c2)CC1
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Into a pressure-tight hydrogenating apparatus 3.5 g (0.009 mole) of 5-{2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-piperidine-1-yl]-ethylamino}-4-chloro-2H-pyridazine-3-one, 350 ml of a solvent mixture (1:1 mixture of methanol and dichloro methane), 0.4 g (0.01 mole) of sodium hydroxide and 7 g of a palladium charcoal catalyst (composition: 8% of palladium, 28% of carbon, 64% of water) are weighed in. The reaction mixture is stirred at a hydrogen pressure of 10 atm. for 16 hours. Hydrogen is removed from the apparatus. The reaction mixture is heated to reflux temperature and stirred at this temperature for 5 minutes. The mixture is filtered hot and the catalyst is washed five times with 350 ml of a 1:1 mixture of methanol and dichloro methane each. The united mother-lyes are evaporated in vacuo. The crude product is dissolved in a 9:1 mixture of 2-propanol and water under stirring and reflux, filtered and the filtrate is evaporated to 100 ml. The mixture is stirred under cooling with icecold water for half an hour. The precipitated crystals are filtered, suspended in a 9:1 mixture of 2-propanol and water and the suspension is acidified by adding concentrated aqueous hydrochloric acid. To the suspension under reflux a 9:1 mixture of 2-propanol and water is added until a clear solution is obtained. The solution is filtered warm, the filtrate is evaporated to 15 ml, the concentrate is stirred under cooling with icecold water and the crystals are filtered off. Thus 1.95 g of the desired compound are obtained. Yield 50.4%. M.p.: 267–269° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.O1CCCC1.O.O.[OH-].[Li+]>C(OCC)(=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)OCC)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1CCC(N2CCC(C(=O)O)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a stirred mixture of [1,4′]Bipiperidinyl-4,1′-dicarboxylic acid diethyl ester (5.51 grams, 17.67 mmol), tetrahydrofuran (34 mL) and water (34 mL) cooled at 0° C., lithium hydroxide monohydrate (742.0 mg, 17.67 mml) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with Ethyl acetate. The two layers were separated, the aqueous layer was acidified with 2N hydrochloric acid to pH: 3-4 and the volatiles were removed under reduced pressure to obtain [1,4′]Bipiperidinyl-4,1′-dicarboxylic acid 1′-ethyl ester (5.0 grams).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[NH:10][C:11]2[C:12]([N:24]=1)=[N:13][CH:14]=[C:15]([C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22])[CH:16]=2)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29].[CH3:23][C:18]1[C:17]([C:15]2[CH:16]=[C:11]3[NH:10][C:9]([CH2:8][NH3+:7])=[N:24][C:12]3=[N:13][CH:14]=2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1noc(C)c1-c1cnc2nc(CNC(=O)OC(C)(C)C)[nH]c2c1
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cnc2nc(C[NH3+])[nH]c2c1
Product: O=C([O-])C(F)(F)F

Procedure:
To a DCM solution (4 mL) of [6-(3,5-Dimethyl-isoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-ylmethyl]-carbamic acid tert-butyl ester (360 mg, 1.048 mmol) was added trifluoroacetic acid (4.0 mL, 51.9 mmol), in a nitrogen atmosphere.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][C@H:38]1[CH2:40][O:39]1>C(O)(C)C.CO>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:37][C@@H:38]([OH:39])[CH3:40])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: C[C@H]1CO1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(C)O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 29.3 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol) (Example 1, step 7, chiral intermediate from peak 1) and triethylamine (20 μL, 0.1 mmol) in isopropyl alcohol (0.10 mL) was added (S)-(−)-methyloxirane (3.2 μL, 0.046 mmol). The resulting mixture was stirred at 90° C. After 90 min, additional (S)-(−)-methyloxirane (6.4 uL) was added and stirred at 90° C. overnight. After cooling, the mixture was diluted with methanol and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6 mg (30%) of the product. The product was isolated as a single diastereomer. LCMS calculated for C22H30 ClN6O2 (M+H)+: m/z=445.2; Found: 445.2.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H:29]([N:31]5[CH:36]=[C:35]([C:37](N)=O)[CH2:34][CH:33]=[CH:32]5)[C@H:28](O)[C@@H:27]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1N=C(N)C2N=CN([C@@H]3[O:58][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.[NH2:93][C@H:94]([C:100]([O-:102])=[O:101])[CH2:95][CH2:96][C:97]([O-:99])=[O:98]>>[CH:32]1[CH:33]=[C:34]2[C:35]([CH2:37][C@@:96]([OH:58])([C:97]([OH:99])=[O:98])[CH2:95][C@H:94]([NH2:93])[C:100]([OH:102])=[O:101])=[CH:36][NH:31][C:29]2=[CH:28][CH:27]=1
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
Production of monatin from indole-3-pyruvate and pyruvate, using BioCatalytics amino acid dehydrogenase enzymes coupled with the C. testosteroni ProA aldolase, was assayed under the following conditions: 6-7 mg/ml dehydrogenase enzyme, 5 mg NADH or NADPH, 50 μg aldolase (unpurified, see Example 7), 3 mM potassium phosphate buffer, 2 mM MgCl2, 4 mg indole-3-pyruvate, and 20 mg pyruvate were added to one mL of AADH reaction buffer (100 mM bicarbonate, pH 9.5, 200 mM NH4Cl). Negative controls contained no amino acid dehydrogenase enzyme. Samples were incubated at 30° C. at 100 rpm overnight. Experiments were performed in duplicate. The dehydrogenases tested were AADH-110, AADH-111, AADH-112, and AADH-113. AADH-110 and 111 have been defined as broad specificity enzymes, while 112 and 113 are glutamate dehydrogenases. AADH-110 produced the most monatin (as measured by LC/MS/MS) in comparison to the negative controls, approximately 0.36 μg/mL. The NADH-utilizing glutamate dehydrogenase, AADH-112, showed higher activity than the NADPH utilizing glutamate dehydrogenase (AADH-113). AADH-111 did not appear to produce more monatin than the negative control under the conditions assayed.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:24]([CH2:26][CH3:27])[CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH2:26]([N:24]([CH3:25])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2N(C)CC)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCN(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 18 h
Yield: 96.6 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(Ethyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (337, 650 mg, 1.77 mmol) is charged with 1,4-dioxane (10 mL) and MeOH (10 mL). A stirring bar is added and stirring is initiated. After dissolution, water (5 mL) is added followed by the LiOH monohydrate (187 mg, 4.46 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (1 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 18 h, the contents of the flask are filtered through a pad of celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed under reduced pressure. This process is repeated 1 time. Pumping to constant weight gives beige solid (0.58 g, 97%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](Cl)(Cl)Cl)[N:8]=1.[CH:17]([OH:20])([CH3:19])[CH3:18]>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:20][CH:17]([CH3:19])[CH3:18])=[O:2])[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Reactant: CC(C)O
Product: CC(C)OC(=O)c1cccc(Cl)n1
Temperature: 135 °C
Reaction time: 3 h

Procedure:
[A1 is N, A2 is Cl—C, A3, A4 and A5 are CH, X is O and R1 isopropyl in the compound of formula I] Concentrated sulfuric acid (98% by weight, 510.2 g, 5.2 mol) is added to 2-chloro-6-trichloromethylpyridine (NP, 924 g, 4 mol) over a period of three hours at 135° C. The resulting mixture is stirred for three hours at 135° C. A viscous melted mass is obtained consisting of a mixture of intermediate IVa1 and Va1 with R1 being H and Hal being Cl, corresponding to an almost quantitative yield based on NP. The mass is added to isopropanol (2145 g) over a period of 30 minutes starting at ambient temperature which is raised to 60-65° C. Remaining isopropanol is removed by distillation under reduced pressure in three hours. The resulting product mixture is added to a mixture of xylene (1800 g) and water (1500 g). Upon heating to 50° C. the organic phase is separated and washed with water (1000 g). The obtained organic phase is dried and concentrated by distillation of xylene under reduced pressure (250 mbar). The resulting product (2070 g) contains 34.1 wt % of isopropyl 2-chloropyrid-6-ylcarboxylate in xylene which corresponds to a yield of 8.4% based on NP and is used for the preparation of N-4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6-ylinecarboxamide without further purification (Examples 9 and 10).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1.CS[C:20](SC)=[CH:21][N+:22]([O-:24])=[O:23]>>[N+:22]([CH:21]=[C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)([O-:24])=[O:23]
Reactant: NCCSCc1ccc(CNCC(F)(F)F)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: O=[N+]([O-])C=C(NCCSCc1ccc(CNCC(F)(F)F)o1)NCCSCc1ccc(CNCC(F)(F)F)o1
Yield: 21.8 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-(2,2,2-trifluoroethyl)-2-furanmethanamine (0.83 g) and 1,1-bis-(methylthio)-2-nitroethene (0.25 g) was heated at 98°-100° for 3 hr. The gummy residue was chromatographed (silica/ethyl acetate then ethyl acetate/ethanol 9:1) and the appropriate eluate evaporated to dryness to give the title compound (0.2 g) as an oil.
Reaction SMILES: FC(F)(F)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Cl[C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.[IH:23]>>[I:23][C:16]1[CH:21]=[C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[OH:3])[N:19]=[CH:18][N:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: I
Product: Oc1ccccc1-c1cc(I)ncn1

Procedure:
The compound was prepared according to Example 1 using 2-trifluoromethoxyphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[N+:15]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
First, 300 g of 9,10-dihydrophenanthrene were dissolved in 2 L of acetic acid, and then 450 mL of fuming nitric acid (d=1.50) were dropped to the mixture. The reaction solution was stirred at room temperature for 7 hours. The reaction solution was poured into 5 L of water, and then the precipitated crystal was separated by filtration and recovered. The resultant crystal was washed with water and methanol, and was then dried under reduced pressure. Thus, 280 g of an orange crystal were obtained (in 74% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.[BH4-].[Na+]>C(O)C.C1COCC1>[OH:1][C:2]1[C:11]([CH:12]([OH:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(=O)oc2c(C(O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
A solution of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (10.0 g, 29.2 mmol, 1.0 eq) in a mixture of ethanol (500 mL) and THF (200 mL) was cooled to 0° C. and sodium borohydride (1.7 g, 45.0 mmol, 1.54 eq) was add portionwise within 1 h. The reaction mixture was allowed to warm up room temperature and stirred for 3.5 h. The reaction was quenched with saturated aqueous ammonium chloride (20 mL). The solvents were removed under vacuum and the residue was partitioned between ice-cold 1N hydrochloric acid (200 mL) and ethyl acetate (500 mL). The organic layer was separated and washed successively with saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified on a silica column eluted with 20-50% ethyl acetate in hexanes, affording 7.1 g of 11a (71% yield). 1H NMR (CDCl3): 1.01 (q, J=7.5 Hz, 6H), 1.46 (s, 3H), 1.50 (s, 3H), 1.61 (m, 2H), 1.88 (m, 2H), 2.78 (m, 1H), 2.89 (m, 1H), 4.96 (d, J=3.5 Hz, 1H), 5.54 (d, J=10.0 Hz, m, 2H), 5.78 (s, 1H), 6.69 (d, J=10.0 Hz, 1H), 10.18 (s, 1H); 13C NMR (CDCl3): 9.57, 14.04, 23.10, 27.47, 28.08, 29.78, 38.59, 70.73, 77.58, 102.85, 107.15, 107.62, 109.12, 116.54, 126.76, 150.89, 151.28, 156.08, 159.70, 162.01; IR: 1683 cm−1; MS (ACPI+): 345 (M+1); Anal. Calcd. for C20H24O5: C 69.75, H 7.02; Found: C 69.90, H 7.05.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[N:34]1([CH:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:41]4[CH2:42][CH2:43][CH:39]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:40]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidin-yl-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H), 0.77 (m, 1H). m/z: 472 [M+H]