Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.O>CS(C)=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:18]2[N:17]=[C:16]([C:15]3[N:14]4[C:10]([S:11][CH:12]=[CH:13]4)=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:21]=[CH:20][N:19]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3sccn23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc(-c3c(-c4ccc(F)cc4)nc4sccn34)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-(4-fluorophenyl)-5-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[2,1-b]thiazole (L) (1.05 g, 2.8 mmol) in dimethylsulfoxide (12.0 mL) is added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.6 mmol) followed by Hunig's Base (0.76 mL, 5.6 mmol). The reaction mixture is sealed and set to shake at 100° C. for 12 hours. After cooling to room temperature, water is added (50 mL) and the aqueous phase extracted with ethyl acetate (4×20 mL). The combined organic phase is washed with a saturated, aqueous, sodium chloride solution (3×50 mL) and dried over anhydrous sodium sulfate. The organic phase is filtered and the solvent evaporated in vacuo. The crude product is purified by silica gel column chromatography eluting with ethyl acetate/hexane (3/2). The compound 4-{4-[6-(4-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (M) (Compound CCXXXIII, Table 2) is obtained as a light yellow solid (1.2 g, 88%); m.p. 209-211° C.;
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([NH2:23])=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.CO.O>[NH2:23][C:20]1[S:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2nnc(N)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a solution [6-(5-amino-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.6 g, 1.72 mmol) in THF (15 mL) and methanol (2 mL) was added a solution of LiOH (0.165 g, 6.87 mmol) in water (15 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours then acidified to pH=2 with dilute hydrochloric acid at 0° C. After removal of the volatile organics, the residue was neutralized to pH 7 using saturated sodium bicarbonate. The precipitated solid was filtered and stirred with ethyl acetate (20 mL) for 1 hour. The solid was filtered, washed with cold ethyl acetate and water then dried to give the product (0.412 g, 75%). 1HNMR (400 MHz, DMSO-d6) δ9.26 (br. s., 1H), 7.32 (d, J=2.05 Hz, 1H), 7.16 (d, J=1.76 Hz, 1H), 7.05 (s, 2H), 5.48 (dd, J=9.37, 2.05 Hz, 1H), 3.04 (dd, J=15.37, 2.49 Hz, 1H), 2.29 (s, 3H), 2.12 (dd, 1H). MS (ESI) m/z=322 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(Cc2ccccc2)CC1

Procedure:
3.4 g of methyl 2-chloronicotinate, 5.5 g of potassium carbonate and 3.5 g of N-benzylpiperazine were reacted in 75 ml of DMF analogously to Example 1a, 6.2 g (100%) of the product being obtained.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:4][CH3:1]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1Br
Temperature: 25 °C

Procedure:
A mixture of K2CO3 (68 g, 0.5 mol), 2-bromo-4-chlorophenol (50 g, 0.24 mol) and MeI (42.6 g, 0.3 mol) in acetone (1000 mL) was heated to reflux for 5 h and then cooled to room temperature. The solid was filtered off and washed with dichloromethane (100 mL×3). The combined filtrate was concentrated to dryness. The residue was diluted with diethyl ether (500 mL) and washed with 1N HCl (100 mL×2), H2O (100 mL×2) and brine (200 mL). The separated organic layer was dried over Na2SO4 and concentrated to give 2-bromo-4-chloroanisole 4a as light yellow liquid. 1H NMR (CDCl3): δ 7.52 (d, J=2.8 Hz, 1H), 7.24 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH:16][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Nc1ccc(F)cc1F
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(F)cc2F)C1
Yield: 18.1 %

Procedure:
The title compound (D31) (90 mg) was prepared according to the experimental procedure described in Description 30 starting from 1-Boc-3-azetidinone (300 mg, 1.75 mmol) and 2,4-difluoroaniline (0.178 ml, 1.75 mmol). Reaction time: 1 week.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@@H:26]([OH:45])[CH2:27][NH:28][C:29]([CH3:44])([CH3:43])[CH2:30][CH2:31][N:32]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[CH:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([C@@H:26]([OH:45])[CH2:27][NH:28][C:29]([CH3:44])([CH3:43])[CH2:30][CH2:31][N:32]2[CH:36]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:34]=[CH:33]2)=[CH:13][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Product: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.7 %

Procedure:
0.10 mL (41 mmol) benzenesulphonic acid chloride were slowly added at 0° C. to a solution of 0.20 g (41 mmol) (R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanol in 5 mL pyridine with vigorous stirring. After the addition was complete the reaction mixture was stirred for 4 h at 0° C. and then poured into 40 mL ice water/ethyl acetate (1:1). The phases were separated and the aqueous phase was extracted three times with 20 mL of ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed using the rotary evaporator. 0.14 g (0.28 mmol, 99%) (R)—N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamide was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.O.Cl>C(O)C.CC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: Nc1ccc(NCC(=O)O)cc1
Reaction time: 0.5 h
Yield: 114.3 %

Procedure:
1 g (5 mmol) of (4-nitrophenyl)glycine is dissolved in 20 ml of ethanol, 5 ml of water and 2.5 ml (2.5 eq) of 5N hydrochloric acid in a 250 ml glass reactor (Paar apparatus). 1 g of palladium-on-charcoal (50% moisture and 10% active) is then introduced. The mixture is hydrogenated under a pressure of approximately 2.76×105 Pa for 1 hour 30 minutes at a temperature of 20° C. After filtering through celite, the filtrate is evaporated to dryness. A white solid is obtained which is taken up in 50 ml of acetone, filtered and dried under vacuum at 40° C. 0.95 g of a white powder is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][CH2:28][OH:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:27][CH2:28][OH:29])[CH2:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: OCCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCO)CC3)c2n1

Procedure:
Prepared similarly to Example 1 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine (for example, as prepared for Intermediate 30) and 2-bromoethanol (commercially available, for example, from Aldrich).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:28][CH2:27][CH2:26]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(I)C=C>C(OCC)(=O)C.CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH:15]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:28][CH:27]=[CH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
Combine (S)-4-benzyl-3-(3,4-dichlorophenyl)acetyl-2-oxazolidinone (13.9 g, 38.2 mmol) and tetrahydrofuran (140 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium bis(trimethylsilyl)amide (42 mL, 1.0 M in tetrahydrofuran, 42 mmol). After 30 minutes, add allyl iodide (19 g, 114.5 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1 hour, partition the reaction the reaction mixture between a saturated aqueous ammonium chloride solution and diethyl ether. Separate the layer, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give (S)-4-benzyl-3-(2-(3,4-dichlorophenyl)pent-4-enoyl)-2-oxazolidinone: Rf=0.50 (silica gel, 20% ethyl acetate/hexane).
Reaction SMILES: C1(=O)CCCC(=O)C1.C1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2C(=O)CC1>>[NH:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:21]1
Reactant: O=C1CCCc2[nH]c3ccccc3c21
Agent: O=C1CCCC(=O)C1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A 0.25 mol/L 1,3-cyclohexanedione/50% sulfuric acid solution was placed in a 200-mL container purged with nitrogen. Then, a 0.25 mol/L phenylhydrazine/50% sulfuric acid solution was added dropwise into the container under stirring at 20000 rpm by CLEARMIX (manufactured by M Technique Co., Ltd.) while the temperature of the liquid in the container was maintained at 25° C. As a result of HPLC analysis, the production rate of 1,2,3,4-tetrahydrocarbazol-4-one was 24% or less.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N
Agent: Cl[Sn]Cl
Solvent: O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N

Procedure:
The title compound was prepared from [4-cyano-5-(methyl-propyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C26) (1.64 g, 4.90 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a dark red oil (1.24 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[CH3:24]>>[CH2:23]([O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:24]
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: CCO
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using the following starting materials: (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid and ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([OH:20])=[C:6]([C:8](=[N:18][NH2:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[S:22](Cl)(Cl)=O>>[Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:18]=[N:19][S:22][C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: COc1ccc(CC(=NN)c2cc(Cl)c(O)cc2O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2snnc2-c2cc(Cl)c(O)cc2O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(5-chloro-2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone hydrazone (2a) (0.1 g, 0.33 mmol) is carefully added to thionyl chloride (1 ml). The reaction mixture is stirred at room temperature for 2 hours. The excess of thionyl chloride is evaporated under reduced pressure, the residue is dissolved in chloroform (10 ml). The organic layer is washed twice with NaHCO3 (sat. aq. 10 ml), then with water (15 ml), dried over Na2SO4, concentrated in vacuo. The residue was purified by dry column chromatography (D. S. Pederson, C. Rosenbohm, (2001) Synthesis, 16, 2431-2434).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: COc1ccccc1CCN
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: COc1ccccc1CCNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-(2-methoxyphenyl)ethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 346.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.66 (br s, 1H); 8.38 (br s, 1H); 8.22 (br s, 1H); 7.88 (d, J=6.7 Hz, 1H); 7.40 (m, 2H); 7.22 (m, 2H); 6.92 (m, 2H); 6.78 (d, J=5.4 Hz, 1H); 5.60 (br s, 1H); 3.88 (s, 3H); 3.78 (m, 2H); 3.03 (t, J=6.7 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-phenoxy-phenol as in Example 18 to afford 0.139 g (52%). 1H NMR (400 MHz, CDCl3); MS (ES−) m/z mass calculated for C30H27O5F 486, found 485 (M−1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]3[CH:21]=[C:20]4[C:15]([CH2:16][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:18][O:19]4)=[CH:14][C:13]=3[F:25])[CH2:8][O:9]2)=[CH:4][C:3]=1[F:26].C([Li])CCC.C1(C)C=CC(S([C:41]#[N:42])(=O)=O)=CC=1>C1COCC1.CCCCCC.CCOCC>[F:26][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:41]#[N:42])[O:9][CH2:8][CH:7]([C:12]1[CH:21]=[C:20]3[C:15]([CH2:16][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:18][O:19]3)=[CH:14][C:13]=1[F:25])[CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCCC1COc2cc(C3COc4cc(Br)c(F)cc4C3)c(F)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC1COc2cc(C3COc4cc(C#N)c(F)cc4C3)c(F)cc2C1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
1.4 g (3.31 mmol) of 7-bromo-6,6′-difluoro-3′-propyl-3,4,3′,4′-tetrahydro-2H,2′H-[3,7′]bichromenyl are dissolved in 20 ml of THF, and 3 ml (4.8 mmol) of a 15 percent solution of n-butyl-lithium in hexane are added at −50° C. The batch is left to stir for 2 h at −70° C., and a solution of 0.9 g (5.00 mmol) of p-toluenesulfonyl cyanide in 10 ml of THF is subsequently added at such a rate that the temperature does not exceed −65° C. After 30 min, the batch is allowed to thaw, diluted with ether and washed with dil. hydrochloric acid. The org. phase is dried over sodium sulfate and evaporated, and the crude product is chromatographed on silica gel with heptane/toluene (2:3), giving 6,6′-difluoro-3′-propyl-3,4,3′,4′-tetrahydro-2H,2′H-[3,7]bichromenyl-7-carbonitrile as colourless crystals of m.p. 122° C.
Reaction SMILES: [CH2:1]([Sn:5](C1C=CC=CC=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[I:24]I>CO>[CH2:1]([Sn:5]([I:24])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: II
Reactant: CCCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: CCCC[Sn](I)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a three-necked flask protected from light, butyltriphenyltin (21.05 g; 51.8 mmol) was dissolved in 50 mL of dry methanol. A solution of iodine (12.06 g; 47.5 mmol) in methanol was then added slowly. After stirring at room temperature during 16 hours, methanol was eliminated under vacuum. The residue was dissolved in petroleum ether and washed with a saturated aqueous solution of sodium thiosulphate. Organic layers were washed with a saturated NaCl solution and dried over MgSO4. Solvent was evaporated and the crude product was distilled using a Kugelrohr apparatus at 60° C. A colourless oil was obtained (22.2 g, 48.6 mmol).
Reaction SMILES: F[C:2]1[CH:3]=[C:4](OC)[C:5](OC)=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:7]=1.CS(O)(=O)=O>>[C:11]1(=[O:13])[C:7]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: COc1cc(F)cc(CCCC(=O)O)c1OC
Agent: CS(=O)(=O)O
Product: O=C1CCCc2ccccc21
Yield: 105.2 %

Procedure:
The product from Example 66 (7.4 g) was cyclized with methanesulfonic acid (75 ml) at room temperature overnight. The reaction was poured onto water and extracted with methylene chloride. The organic layer was separated, washed with brine, dried and evaporated to afford 4.7 g impure tetralone. Purification was achieved by extraction with hot hexane to obtain 3.7 g pure compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)=[O:21]
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C(C)(C)C)c3)nn12
Reaction time: 3 h

Procedure:
To solution of 8.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 4.6 ml of trimethylacetyl chloride and 6.8 ml of diisopropylethylamine. The mixture was stirred for 3 hours and then poured into 200 ml of aqueous saturated sodium bicarbonate. The organic layer was separated, dried, and the solvent was removed in vacuo. The residue was recrystallized from dichloromethane-hexane to give 9.2 g of white crystals, mp 256°-258° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][C:19]([O:47][CH3:48])=[C:20]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.N#N>CO.COCCOC.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][C:19]([O:47][CH3:48])=[C:20]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: COCCOC
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(O)c3)nc2cc1OC
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A suspension of tert-butyl 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.70 g, 4.17 mmol) in MeOH (400 mL) and DME (200 mL) was added Pd/C (10%, wet, 0.500 g) under an atmosphere of N2. The N2 was exchanged for H2 and the mixture was stirred under an atmosphere of H2 (balloon pressure) overnight. The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.25 g, 4.04 mmol, 97%). MS 558 (M+1). HPLC retention time 6.44 mins.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=S)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[O-]CC.[Na+]>C(O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 4,5-bis(4-fluorophenyl)-1H-imidazole-2-thione (8.0 g, 0.028 mol), sodium ethoxide (1.9 g, 0.028 mol) and 1,2-diiodotetrafluoroethylene (4.9 g, 0.014 mol) in ethanol (100 ml) was refluxed for two hours and then cooled. The yellow precipitate was collected, washed with ethanol and recrystallized from chloroform to give the title compound, m.p. 234°-236°.