Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])#[CH:15]>C(O)(C)(C)C>[ClH:1].[C:14]([C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1)#[CH:15]
Reactant: C#Cc1cccc(N)c1
Reactant: COc1ccc2c(Cl)ncnc2c1
Solvent: CC(C)(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)ccc23)c1
Product: Cl

Procedure:
4-Chloro-7-methoxyquinazoline (274 mg, 3.72 mmol) and 3-ethynylaniline (436 mg, 3.72 mmol) were refluxed in 15 mL of tert-butyl alcohol for 3 hours, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 977 mg (84%); mp 229°-231° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 49.7 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (0.059 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.041 g, 0.090 mmol, 49.6% yield) as a white solid. The mother liquor was concentrated to small volume, diluted with IPA, stirred for 30 minutes, and filtered to give a second batch of 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.011 g, 0.024 mmol, 13.31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (t, J=5.56 Hz, 1H), 7.88-7.99 (m, 1H), 7.78 (s, 1H), 7.37-7.57 (m, 2H), 7.30 (s, 1H), 4.55 (d, J=5.49 Hz, 2H). LC-MS (ES−) m/z 455.10, 457.03 [M−1]. LC-MS (ES+) m/z 456.99, 459.87 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:64][CH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH3:76])([CH3:75])[O:73][B:72]([OH:77])[C:71]=2[CH:78]=1>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:64][CH2:65][CH2:66][C:67]5[CH:68]=[CH:69][C:70]6[C:74]([CH3:75])([CH3:76])[O:73][B:72]([OH:77])[C:71]=6[CH:78]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(O)c2cc(CCNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.76 mmol) and HATU (456 mg, 1.2 mmol) in DMF (18 mL), DIPEA (310 mg, 2.4 mmol) can be added. The reaction mixture can be stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) can be added. The reaction mixture can be continued to stir overnight. Water can be added and the mixture can be extracted three times with ethyl acetate. The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[C:32]([C:30]1[CH:29]=[CH:28][C:27]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[C:26]([CH3:25])[CH:31]=1)#[N:33]
Reactant: Cc1cc(C#N)ccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: Cc1cc(C#N)ccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 14 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-methyl-4-cyanophenylboronic acid (available from Aldrich Chemical Company, Inc.; 64 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-methyl-biphenyl-2-carboxylic acid (13 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.75-7.83 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1>>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C:31]5[N:30]=[CH:29][C:28]6[O:27][CH2:26][CH2:25][O:24][C:33]=6[CH:32]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Product: Cl
Product: O=c1ccc2ncc(Cl)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCCO3)[C@H](O)C1
Yield: 58 %

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) according to the general method of Example 2(h), in 58% yield
Reaction SMILES: O[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:26][CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of tert-butyl [2,3-dihydro-2-(2-hydroxyethyl)-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (7.7 g) and carbon tetrabromide (8.0 g) in tetrahydrofuran (80 mL) was added 6.3 g of triphenylphosphine under ice-cooling and the mixture was stirred for 30 minutes. This reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97:3 to 4:1) to provide 7.5 g of the title compound. Yield 82%.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:9](=[NH:11])[NH2:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[NH:10][C:9]([C:4]2[C:3]([F:2])=[CH:8][CH:7]=[CH:6][N:5]=2)=[N:11]1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1ncccc1F
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Yield: 45.1 %

Procedure:
3-fluoropicolinimidamide hydrochloride (5.53 g, 31.5 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (5.56 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>O1CCCC1>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:23])[CH2:21][CH3:22]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(C(=O)O)ccc1OC
Temperature: 25 °C
Yield: 97.1 %

Procedure:
0.6 g 3-amino-4-methoxybenzoic acid (1.0 g, 6 mmol) is dissolved in dry THF (tetrahydrofuran) in a 25 ml flask, triethylamine (1.2 ml, 12 mmol) is subsequently added to obtain transparent yellow solution. The mixture is stirred under nitrogen protection, propionyl chloride (0.78 ml, 9 mmol) is added into the flask in an ice-water bath. After finishing addition of propionyl chloride the mixture is naturally raised to room temperature. The reacted mixture is filtered, the filtrate is evaporated to dryness and separated using a silica column to obtain 3-propionamido-4-methoxybenzoic acid 1.3 g (yield: 67%).
Reaction SMILES: [NH2:1][C@@H:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])OC(C)(C)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]=O)=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH3:22][O:21][C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:1]2[C:5](=[O:11])[CH2:4][CH2:3][C@@H:2]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:25][CH:24]=1)=[O:20]
Reactant: COC(=O)c1ccc(CC=O)cc1
Reactant: CC(C)(C)OC(=O)CC[C@@H](N)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CCN2C(=O)CC[C@@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of H-D-Glu(OtBu)-OtBu (0.5 g, 2.23 mmol) in MeOH (15 mL) were added 4-carbomethoxyphenylacetaldehyde (obtained from methyl 4-formyl benzoate as described in J. Med. Chem. 1989, 32, 1277-1283) (0.4 g, 2.23 mmol), acetic acid (0.15 mL, 2.67 mmol), and NaCNBH3 (3.3 mL, 1.0 M THF solution, 3.3 mmol). The resulting solution was stirred at RT for 3 h then was diluted with EtOAc (100 mL) and washed with water (50 mL), and brine (50 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo. The crude oil was diluted with xylene and the solution refluxed for 5 h. This solution was concentrated under reduced pressure and purified by silica gel column chromatography using EtOAc/hexane as eluent to afford the title compound (0.75 g, 75%) as a white solid. Rf0.45 (EtOAc/hexane 1/1); 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.95-2.05 (m, 1H), 2.10-2.20 (m, 1H), 2.25-2.35 (m, 1H), 2.40-2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.10-3.20 (m, 1H), 3.82 (dd, 1H), 3.91 (s, 3H), 3.90-4.01 (m, 1H), 7.25 (d, 2H), 7.96 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([Cl:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>C(Cl)Cl.CO>[Cl:38][C:32]1[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=[C:30]([NH:29][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)[CH:31]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (Step 9.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.91 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 541/543 [M+H]+ (LC-MS 2); Rf=0.32 (CH2Cl2/MeOH 9:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14](=[O:16])=[O:15]>C(OCC)C.CCCCCC>[Br:8][C:4]1[N:3]=[C:2]([C:14]([OH:16])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cccc(Br)n1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2,6-dibromopyridine (19 g) in diethylether (200 ml) was added to a mixture of n-butyl lithium (130 ml of a 1.6M solution in hexane) and diethylether (200 ml) cooled to -50° C. The resulting solution was stirred at -50° C. for 10 minutes before pouring onto a slurry of diethyl ether (100 ml) and dry-ice. The mixture was allowed to warm to room temperature and filtered. The resulting solid was dissolved in 2N sodium hydroxide (350 ml) and extracted with diethyl ether (2×300 ml). The aqueous layer was separated and acidified with 2N hydrochloric acid. The resulting precipitate was filtered and washed with water to give 6-bromo-2-pyridine carboxylic acid (7.25 g): NMR (d6 DMSO) δ 7.69(d,1H), 7.95(d, 1H), 8.05(dd, 1H); m/e 202(M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]3[CH:17]=[CH:18][S:19][C:11]=3[S:10]2(=[O:21])=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Li])CCC.[S:27](=[O:29])=[O:28].[NH2:30]OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C1COCC1>[OH:16][CH2:15][C:14]1[N:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:10](=[O:20])(=[O:21])[C:11]2[S:19][C:18]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][C:12]=2[CH:13]=1
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Reactant: O=S1(=O)c2sccc2C=C(CO)N1CCN1CCOCC1
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CCN1CCOCC1)C(CO)=C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a mixture of the product from Step D (3.25 g, 9.85 mmol) in anhydrous THF (40 mL) under nitrogen at -70° C. was added n-butyllithium (2.5M in hexanes, 9.06 mL, 22.7 mmol). The mixture was stirred for 7 min before sulfur dioxide gas was passed over the solution for about 5 min. The resulting mixture was warmed to ambient temperature and evaporated to a residue which was mixed with ice-water (150 mL), hydroxylamine-O-sulfonic acid (3.34 g, 29.6 mmol) and sodium acetate (6.20 g, 45.6 g) and stirred for 4 h at ambient temperature. The reaction mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried over magnesium sulfate and evaporated to a residue which was purified by column chromatography (silica, 5% to 10% methanol/methylene chloride) to give a glass (3.10 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Mg+2].[Cl-].[Cl-].[C:12](#N)[CH:13]=[CH2:14].[OH-:16].[Na+]>C1COCC1.CCN(CC)CC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:8][CH2:14][C:13](=[O:16])[CH2:12]2
Reactant: Oc1ccccc1Br
Reactant: [OH-]
Reactant: C=CC#N
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2c(Br)cccc2C1

Procedure:
8-Bromochroman-3-one 28B was prepared from 2-bromophenol in a manner similar to that described in the literature (J. Med. Chem., 1988, 689): Reaction of 2-bromophenol with paraformadehyde (MgCl2, NEt3, THF, 75° C., 4 h), followed by treatment with acrylonitrile (neat, Dabco, 95° C., 18 h), and hydrolysis with 10% NaOH (100° C., 4 h) afforded 28A. Compound 28A was reacted with DPPA (NEt3, toluene, 110° C., 2 h) followed by treatment with 6N HCl (85° C., 2 h) to afford 8-bromochroman-3-one 28B.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=4)=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1>C(OCC)(=O)C.C1C=CC=CC=1.CO.[Pd]>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)=[CH:16][CH:17]=2)[NH:21][N:20]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1O
Temperature: 23 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole (25 mg, 0.055 mmol) was dissolved in a mixture of ethyl acetate (2 mL), benzene (2 mL) and methanol (2 mL). To this solution was added palladium on carbon (25 mg, 10% wt) and the reaction vessel was vacuum/purged with hydrogen gas for five cycles. The reaction mixture was allowed to stir for 3 days (d) at 23° C. and was filtered through a plug of Celite. Concentration and purification by silica gel chromatography afforded 3-(Naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole (8 mg, 40%): 1H NMR (CDCl3) δ 10.3 (bs, 1H), 8.50 (s, 1H), 8.20 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8 Hz), 7.90 (m, 1H), 7.7–6.8 (m, 9H), 3.98 (s, 3H). MS (ES) [m+H]/z Calc'd 367. found 367. [m−H]/z Calc'd 365. found 365.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOCC.O>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Cc2ccccc2)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: OCc1csc(Cc2ccccc2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
90 ml of a toluene solution of 2 M/liter of diethyl sodium aluminum dihydride was added dropwise at -10° C. to a solution of 20 g of the product of Step A in 100 ml of toluene and the mixture was stirred at -5° C. for one hour. 150 ml of aqueous 2N hydrochloric acid were added dropwise to the mixture at -20° C. and then ether and water were added thereto. The mixture was filtered and the organic phase of the filtrate was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 7-3 methylene chloride-ethyl acetate mixture to obtain 13.6 g of (2-benzyl-4-thiazolyl)-methanol melting about 50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=O)=O.OS(O)(=O)=O.O.C(Cl)Cl>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[SH:11]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S)c1
Reaction time: 8 h

Procedure:
16 g of 2,5-dimethoxybenzene-sulphonyl chloride are dissolved in 100 ml of THF, while stirring, and a mixture of 20 ml of concentrated H2SO4 and 60 ml of water is then added, followed by 25 g of zinc dust, added in portions at 50°-55° and stirring is continued overnight at 20°. The THF is then stripped off and the mixture is worked up with water and methylene chloride to give 2,5-dimethoxythiophenol, b.p. 106°-108°/0.3 mm.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N+](=[CH2:42])=[N-]>C(Cl)Cl>[CH3:42][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C@@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:14]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:15][C@@H:2]1[OH:1]
Reactant: C=[N+]=[N-]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: ClCCl
Product: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)C(C)CC=C(C)C)[C@H](OC2CCCCO2)C[C@@H]1O

Procedure:
A solution of 1.55 g of (13E)-(8R,9S,11R,12R,-15S,16RS)-9-hydroxy-16,19-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoic acid in methylene chloride was treated with ethereal diazomethane solution until the evolution of nitrogen ceased and the solution assumed a permanent yellow color. After removal of excess diazomethane as well as the solvent, the residue (1.58 g) was used without further purification in the subsequent reaction stage.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN1C(=O)CCC1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:27][CH:26]=2)[S:11][C:12]=1[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccc(CBr)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccc(Cn2ccnc2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Compound 18 (880 mg, 2.00 mmol) was suspended in NMP (10 mL), and imidazole (408 mg, 6.00 mmol) was added thereto, followed by stirring at 65° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature and then poured into water, and the deposited precipitate was collected by filtration. The resulting precipitate was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 19 (538 mg, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(NCC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3ccc(I)cc23)c1
Reactant: C#Cc1ccccn1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C#Cc1cccc(Nc2ncnc3ccc(C#Cc4ccccn4)cc23)c1

Procedure:
The title compound was synthesized according to the method of Example 2 using (3-Ethynyl-phenyl)-(6-iodo-quinazolin-4-yl)-amine (125 mg, 0.506 mmol), 2-ethynyl-pyridine (66 mg, 0.505 mmol) and diethyl amine (72 mg, 0.99 mmol) in 2 mL, of DMF.