Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].S(Cl)([Cl:23])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCOC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCOC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
4-(Trans-4-(propoxymethyl)cyclohexyl)benzoic acid (2.0 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.9 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(trans-4-(propoxymethyl)cyclohexyl) benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CCOCC1)CC3
Reaction time: 4 h

Procedure:
A mixture of 10 g (0.043 m) of 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 11.2 g (0.06 m) of N-(2-chloroethyl)-morpholine HCl and 14.2 g of triethylamine (0.14 m) in 170 ml of abs. EtOH was refluxed with stirring and protection from mositure for 4 hours. The reaction was filtered hot, cooled slightly and treated with dry HCl. The resulting precipitate was filtered and washed with EtOH, then ether; yield 14.6 g (81%). Crystallization from methanol afforded analytical material, mp 237°-40°C.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[CH2:3][CH:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:5]1[C:6]2=[O:11].[N+:17]([O-])([O-:19])=[O:18].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[N+:17]([C:9]1[CH:8]=[C:7]2[C:2]([CH2:3][CH:4]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:5]3[C:6]2=[O:11])=[CH:1][CH:10]=1)([O-:19])=[O:18]
Reactant: O=C1c2ccccc2CC2CCCCCN12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=C1c2cc([N+](=O)[O-])ccc2CC2CCCCCN12
Reaction time: 8 h

Procedure:
To a solution of 8,9,10,11,11a,12-hexahydro-7H-azepino[1,2-b]isoquinolin-5-one (2.50 g, 11.6 mmol) in concentrated sulfuric acid (30 ml) at 0° C. was added in a single portion potassium nitrate (1.23 g, 12.2 mmol). After the reaction mixture had stirred overnight, it was poured onto ice and basified with concentrated ammonium hydroxide. The aqueous phase was extracted twice with dichloromethane, dried (magnesium sulfate), and concentrated to leave about 15 ml of solvent. Hexanes (100 ml) was added and the solution was placed in the freezer. The precipitated product was collected and dried to give the title compound as a yellow solid (1.94 g, 64%), m.p. 117.5-9° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N+:15]=3[O-])[C:7]=2[CH:25]=1)#[N:2].CC1(C)CC(C2C=CC=CN=2)C2C=C(C(O)=O)C=CC=2O1.CC(C)(OC1C=CC(C#N)=CC=1)C#C>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:10]([CH3:13])([O:11][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:7]=1)[C:9]#[C:8][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CC1(C)C=C(c2ccc3ccccc3[n+]2[O-])c2cc(C#N)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1ccc2ccccc2n1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 5.1 g of 2-iodoquinoline were added at room temperature to a solution of 18 mg of palladium(II) chloride, 52 mg of triphenylphosphine and 38 mg of copper(I) iodide in 100 ml of diethylamine. 3.7 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were added. After stirring at room temperature for 18 hours the mixture was evaporated and the residue was dissolved in ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 5.8 g of 4-[1,1-dimethyl-3-(2-quinolyl)-2-propynyloxy]benzonitrile as a yellow gum. (B) 5.8 g of 4-[1,1-dimethyl-3-(2-quinolyl)-2-propynyloxy]benzonitrile were heated at reflux for 2 hours in 50 ml of dichlorobenzene. The mixture was allowed to cool to room temperature and was then evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) for the elution. The product was recrystallized from isopropanol to give 2.1 g of 2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile of melting point 102°-104° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:21][O:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[N:18][CH:17]=1
Reactant: COc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cncc(N2CCNCC2)n1

Procedure:
Prepared in analogy to example 4.10 (c) from 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 195.1 (MH+, 80%)
Reaction SMILES: BrCBr.Cl[Si](C)(C)C.I[CH:10]1[CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].I[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[Zn].[O-]S([O-])(=O)=O.[Zn+2]>[CH:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:13]2[CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC1I
Reactant: O=Cc1ccc(I)cc1
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Zn+2]
Solvent: BrCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C=O)cc2)C1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Zinc dust (253 mg) was stirred under nitrogen overnight. To this was added DMF (5 ml) and dibromomethane (55 mg) dissolved in DMF (1 ml) and the mixture warmed to ˜70° C. The reaction mixture was cooled to room temperature and chlorotrimethylsilane (32 mg) in DMF (1 ml) added and stirred at room temperature for 15 minutes. To this was added 2-iodo-N-Boc-azetidine (Billotte, S., Synlett, 1998, 379-380) (1.04 g) in DMF (5 ml). The reaction mixture warmed to 40° C. and the mixture sonicated for 30 minutes during which time the zinc powder dissolved to leave a hazy solution. To the solution of zincate was added 4-iodobenzaldehyde (Preparation 43) (851 mg in 5 ml DMF), tri-2-furylphosphine (35 mg in 1 ml DMF) and Pd(dbq)2 (42 ml in 1 ml DMF). The resulting mixture was heated at 60-70° C. for 4 hours, cooled to room temperature and partitioned between ammonium chloride solution and diethyl ether, and the aqueous layer was extracted with diethyl ether (3×). The combined organic extracts were dried (Na2SO4), evaporated in vacuo and purified over silica (pentane:ethyl acetate; 4:1) to afford the title compound as a mobile oil, 626 mg.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1.C(=O)([O-])O.[Na+].Cl>C(OCC)C>[CH2:5]([O:4][C:2]([N:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 72 %

Procedure:
A diethyl ether (50 ml) solution of benzyl chloroformate (36 g, 0.21 mols) was dropwise added to an aqueous solution (200 ml) of isonipecotic acid (25 g, 0.19 mols) and sodium hydrogencarbonate (49 g, 0.58 mols) with stirring at room temperature. After the addition, this was further stirred at room temperature for 15 hours. The reaction mixture was acidified with concentrated hydrochloric acid added thereto, and then extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether/hexane, and taken out through filtration. A colorless crystal of N-benzyloxycarbonylisonipecotic acid (36 g, 71%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Cl.[NH2:53][NH:54][C:55]([NH2:57])=[O:56].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[NH2:53][NH:54][C:55]([NH2:57])=[O:56].[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([OH:18])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:37])([F:38])[F:36])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNC(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 22; 250 mg, 0.4 mmol), trifluoroacetic acid (0.8 ml) and dichloromethane (1.2 ml) was stirred at room temperature overnight and concentrated in vacuo. The residue was treated with semicarbazide hydrochloride (355 mg, 3.2 mmol), triethylamine (1 ml, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (457 mg, 4.2 mmol), and 4-N,N-dimethylaminopyridine (35 mg, 0.28 mmol). The mixture was stirred at room temperature over weekend, quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (278 mg, 55%).
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH3:8][C:9]1[NH:10][C:11]([CH3:31])=[C:12]([C:27]([O:29][CH3:30])=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1>[CH3:8][C:9]1[NH:10][C:11]([CH3:31])=[C:12]([C:27]([O:29][CH3:30])=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:2](=[O:3])[CH3:1])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(C)=O)c1

Procedure:
Under inert gas atmosphere Ac2O (43 mcl) is added to a stirred solution of (-)-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(3-aminophenyl)-1,4-dihydropyridine (100 mg) in pyridine (ml 1). 90 minutes after dilution with water (ml 50), extraction with AcOEt (3×10 ml) and crystallization from Et2O 70/EtOH 10, give mg 85 of +)-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(3-acetylaminophenyl)-1,4-dihydropyridine m.p. 197°-199° C. [α]D =+0.87°, [α]578 =+2.00°, [α]546 =+1.64° c=2.2 DMF.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH:14](C1NC=C(C(OCC)=O)N=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C1C=CC=C2C=1CC(Br)C2=O)=O)C1C=CC=CC=1.[CH2:52]([O:54][C:55]([C:57]1[NH:58][CH:59]=[CH:60][N:61]=1)=[O:56])[CH3:53]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH:14]([C:59]1[N:58]=[C:57]([C:55]([O:54][CH2:52][CH3:53])=[O:56])[NH:61][CH:60]=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: CCOC(=O)c1c[nH]c(C2Cc3c(C(=O)NCc4ccccc4)cccc3C2=O)n1
Agent: O=C(NCc1ccccc1)c1cccc2c1CC(Br)C2=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C2Cc3c(C(=O)NCc4ccccc4)cccc3C2=O)c[nH]1

Procedure:
4-Benzylcarbamoyl-2-(ethoxycarbonylimidazolyl)-1-indanone can be prepared in the following way: a mixture of 0.5 g of 4-benzylcarbamoyl-2-bromo-1-indanone, 0.37 g of 2-ethoxycarbonylimidazole and 10 ml of toluene is heated at reflux for 12 hours. The reaction mixture is concentrated on a rotary evaporator. Dichloromethane is added to the evaporation residue, filtration is carried out and the filtrate is washed with distilled water, dried over sodium sulphate and evaporated on a rotary evaporator. The brown oil obtained (0.26 g) is purified by chromatography on a silica column (diameter: 1.5 cm, height: 30 cm), elution being carried out with a dichloromethane/methanol (95/5 by volume) mixture. The foamy product obtained is triturated with 5 ml of ethyl acetate, filtered and the solid is washed with ethyl acetate (2×5 ml) and dried at 50° C. under vacuum (1 mm Hg; 0.13 kPa). 0.07 g of 4-benzylcarbamoyl-2-(2-ethoxycarbonylimidazolyl)-1-indanone is obtained in the form of an orange solid melting at 218° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[C:27]([O:30][CH2:31]C)(=O)C.Cl>C1COCC1.[Cl-].[Na+].O>[CH3:27][O:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2
Reactant: CCOC(C)=O
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc2c1C(=O)OC2

Procedure:
4-Hydroxy-1,3-dihydro-2-benzofuran-1,3-dione (685 mg, 4 mmol) was dissolved in dry THF (30 mL) at −78° C. K-Selectride 1M solution in THF (13 mL, 13 mmol) was added drop wise in 20 min then the mixture was warmed from −78° C. to −30° C. over 3 hrs. The final mixture was poured into ethyl acetate (100 mL), brine (25 mL) and a 3M hydrochloric acid solution (25 mL). The organic layer was collected, washed with brine and evaporated to dryness. The resulting compound was dissolved in MeOH (20 mL) and treated under stirring with a 3M hydrochloric acid solution (10 mL). The mixture was then diluted with ethyl acetate (100 mL) and brine (25 mL), the organic layer was collected and evaporated under vacuum. The residue was purified by flash chromatography on silica gel using dichloromethane as eluent affording the phenol intermediate (430 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6](C(OC(C)(C)C)=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.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>[Cl:18][C:19]1[C:24]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:2]=2)[NH:8][N:7]=[CH:6]3)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(Br)ccc12
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Yield: 74.3 %

Procedure:
Analogous to the reaction conditions and work-up procedures used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, 5-(2-chloropyridin-3-yl)-1H-indazole was obtained by heating the mixture of tert-butyl 6-bromo-1H-indazole-carboxylate (7.3 g, 24.6 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (7.0 g, 29.5 mmol), Pd(PPh3)4 (2 g, 1.7 mmol) and aq.Na2CO3 (44 mL, 88 mmol) in 1,4-dioxane (200 mL) under argon atmosphere. The crude concentrate that was obtained after the extractive work-up dissolved in CH2Cl2, adsorbed on to silica gel and dried. Subsequent purification by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent gradient upon dry powder loading) provided 5-(2-chloropyridin-3-yl)-1H-indazole as a white solid (4.2 g, 74%). 1H NMR (DMSO-d6): δ 13.21 (s, 1H), 8.43 (dd, 1H, J=1.7 and 4.7 Hz), 8.12 (s, 1H), 7.93 (dd, 1H, J=1.7 and 7.6 Hz), 7.84 (d, 1H, J=8.5 Hz), 7.59 (s, 1H), 7.52 (dd, 1H, J=4.7 and 7.6 Hz), 7.17 (d, 1H, J=8.5 Hz).LCMS: rt 6.17 min (A), purity 98%, MS (m/e) 230 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[C:34]1[O:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24]([C:37]4[O:38][C:34]([CH:30]5[O:31][CH2:32][CH2:33][O:29]5)=[CH:35][CH:36]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Prepared according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine)palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added to facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellow solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1 (s, 1H), 8.85 (d, 1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44 (d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74 (d, 1H), 6.01 (s, 1H), 5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MS m/z 482 (M−1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.Cl.[NH+]1C=CC=CC=1.O>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C(=O)O)O2
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1CCc2cc(O)ccc2O1
Yield: 90.1 %

Procedure:
(RS)-6-Methoxy-chroman-2-carboxylic acid (1.12 g, 5.37 mmol) and pyridinium hydrochloride (11.2 g, 96.6 mmol) were heated together at 180° C. for 2 hr under argon with stirring. After cooling to ambient temperature H2O (100 ml) and EtOAc (50 ml) was added and shaken. The aqueous phase was extracted with EtOAc (50 ml) and the combined organic extracts were washed with satd. NaCl solution (50 ml) and then dried with Na2SO4 and evaporated to afford (RS)-6-hydroxy-chroman-2-carboxylic acid as white crystals (0.94 g, 4.84 mmol, 90%) Mp. 175-177° C., MS m/e=194.1 (M+).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][C:15]1[C:19](B(O)O)=[C:18]([CH3:23])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[C:18]([CH3:23])[O:17][N:16]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(-c2c(C)noc2C)cc1C=O
Yield: 75 %

Procedure:
Ex-33A: 5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 3,5-dimethyl-isoxazole-4-boronic acid in a similar manner as described in Ex-3A, 75% yield. 1H-NMR (CDCl3) δ 10.34 (s, 1H), 7.63 (s, 1H), 6.52 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 2.12 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([Cl:18])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[N:22]=[C:23]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:24][C:25]=1[CH2:26][CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:27][CH2:26][C:25]3[S:24][C:23]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=4)=[N:22][C:21]=3[CH3:20])[CH:15]=2)[C:10]([Cl:18])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(Cl)cn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (3-chloro-6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (3-chloro-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH2:38])[CH:37]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[Cl:39][C:35]1[S:34][C:33]([S:30](=[O:32])(=[O:31])[NH:29][C:26]([CH3:27])([CH3:28])[CH2:25][OH:24])=[CH:37][C:36]=1[NH:38][C:21]([C:20]1[CH:19]=[N:18][N:11]2[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][C:10]=12)=[O:22]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 605.8 [(M−H)−]; mp 272° C.