Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[C:5]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH2:30])=[O:29])[C:21]=3[CH:20]=2)=[N:6][C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:8][CH:9]=1.[BH4-].[Na+].[ClH:33]>CO.ClCCl>[ClH:3].[ClH:33].[Cl:3][C:4]1[C:5]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH2:30])=[O:29])[C:21]=3[CH:20]=2)=[N:6][C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:1])[CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: NC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aqueous formaldehyde (37.4% or 13.5 M, 0.134 mL, 1.80 mmol) is added to a stirred solution of 2-[5-chloro-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide (150 mg, 0.361 mmol) in CH3OH (15 mL) and dichloromethane (15 mL) at room temperature to form a light suspension. The mixture is allowed to stir for 90 minutes. The mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (68.1 mg, 1.80 mmol). The mixture is stirred at 0° C. for 1 hour, then allowed to slowly warm up to room temperature to form a clear solution. After concentration, the crude product is subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 4-12%, to give the desired methylated product as a yellowish solid. The free base is dissolved in CH3OH (20 mL) and dichloromethane (20 mL) then treated with 12 N HCl (0.30 mL) to form a yellow solution. After concentration and vacuum drying at 60° C., the title compound is obtained as a yellow solid (174 mg, 95% yield). ES+(m/z) 430 (35Cl) and 432 (37Cl) [M(free base)+H].
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([S:11]([N:14]3[CH2:23][CH2:22][C:21]4[C@:16]([CH2:34][OH:35])([CH2:17][C:18]5[CH:26]=[N:25][N:24]([C:27]6[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=6)[C:19]=5[CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:37][C:38]1[O:39][CH:40]=[CH:41][N:42]=1>>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([S:11]([N:14]3[CH2:23][CH2:22][C:21]4[C@:16]([CH2:34][O:35][CH2:37][C:38]5[O:39][CH:40]=[CH:41][N:42]=5)([CH2:17][C:18]5[CH:26]=[N:25][N:24]([C:27]6[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=6)[C:19]=5[CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=S(=O)(c1ccc(N2CCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reactant: ClCc1ncco1
Product: O=S(=O)(c1ccc(N2CCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COCc2ncco2)C1

Procedure:
The title compound was prepared by the method of Preparation 2b using [(R)-6-(6-azetidin-1-yl-pyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthal-en-4a-yl]methanol and 2-chloromethyloxazole. LCMS (Method C): 577 (M+H)+, Retention time 10.2 minutes.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].C[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([NH:26][C:27]([C:29]4([C:32]([NH:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[O:33])[CH2:31][CH2:30]4)=[O:28])=[C:21]([F:42])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[C:9]([CH3:43])=[N:8]1.[CH3:44]S(O)(=O)=O>C1COCC1.CCOCC>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[CH3:44][N:8]1[C:9]([CH3:43])=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([NH:26][C:27]([C:29]4([C:32]([NH:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[O:33])[CH2:30][CH2:31]4)=[O:28])=[C:21]([F:42])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:11]=[N:7]1
Reactant: Cc1nn(C)cc1-c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)cnn1C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
N-(4-(2-(1,5-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide from Example 49 (0.081 g, 0.155 mmol) was dissolved in THF (2.5 ml) and warmed until reflux. Methanesulfonic acid (10.09 μl, 0.155 mmol) was added and the mixture cooled to RT. The mixture was slowly diluted with Et2O (5 ml). A precipitate immediately began to form upon addition. After the addition was complete, the mixture was sonicated for 20 min. The precipitate was filtered off to yield N-(4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide mesylate (79 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.72 (s, 1H), 8.52 (d, 1H), 8.20-8.14 (m, 2H), 7.63-7.56 (m, 3H), 7.25 (s, 1H), 7.18-7.14 (m, 2H), 6.99-6.94 (m, 1H), 3.74 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 2H); MS (ESI) m/z: 522.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=3[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: Oc1ccccn1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccn2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-hydroxypyridine as in Example 45 to afford 0.015 g (10%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO5F3 523, found 524 (M+1, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[S:9][C:10]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[C:11]([C:13](OC)=[O:14])[N:12]=1.O>C1COCC1>[CH3:7][C:8]1[S:9][C:10]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[C:11]([CH2:13][OH:14])[N:12]=1
Reactant: COC(=O)c1nc(C)sc1-c1cccc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2sc(C)nc2CO)c1
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a stirred suspension of lithium aluminiumhydride (139 mg, 3.64 mmol) in THF (5 mL) a solution of methyl 2-methyl-5-m-tolylthiazole-4-carboxylate [1007873-98-4] (600 mg, 2.43 mmol) in THF (5 mL) was added at −25° C. and stirred for 30 min. Then water (5 mL) was added dropwise and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 50% ethyl acetate in hexane) to yield the title compound (300 mg, 56%). [LCMS RtF=0.32 min, [M+H]+=219.9; TLC Rf=0.20 (methanol/chloroform 10:90)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12](C)([C:18](OCC)=O)[C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH3:18])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 82.3 %

Procedure:
A solution of compound (26a) (10.8 g, 32.6 mmol) in acetic acid (36 mL), and concentrated sulfuric acid (10 mL), and water (26 mL) were treated in the same manner as in (b) in Production Example 1 to give 6.2 g (82%) of compound (27a) as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:24][C:25]1[N:34]([CH2:35][C:36]#[CH:37])[C:33](=[O:38])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:37]#[C:36][CH2:35][N:34]3[C:33](=[O:38])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]3[CH3:24])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCn1c(C)nc2ccccc2c1=O
Product: Cc1nnc2n1-c1ccc(C#CCn3c(C)nc4ccccc4c3=O)cc1C(c1ccccc1F)=NC2
Yield: 57 %

Procedure:
This compound was obtained by coupling 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,-4]triazolo[4,3-a][1,4]benzodiazepine with 2-methyl-3-(2-propynyl)-4(3H)-quinazolinone [ref. B. Danielsson, L. Kronberg and B. Akerman, Acta Pharm. Suecica, 6, 379, (1969)] as described in ex. 17. It was isolated in 57% yield and crystallized from ethyl acetate. m.p. 241°-244° C. with decomposition. The crystals contained 0.66 molar amounts of water.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:32][CH3:33])[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:47]([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[CH:47]([N:37]1[CH2:36][CH2:35][CH:34]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:32][CH3:33])[CH2:14][CH2:13]2)=[O:11])[CH2:39][CH2:38]1)([CH3:49])[CH3:48]
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCNCC2)CC1
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g of 4-(1-(4-Fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine hydrochloride obtained in Example 11(5) was dissolved in 2 ml of dimethylformamide, and 93 mg of potassium carbonate and 41 μl of 2-iodopropane were added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 0.15 g of 1-isopropyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:23]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[CH:26]=[CH:25][C:24]=1[CH3:32])[CH2:9][C:10]([N:12]([N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CO[C:36](OC)([N:38](C)C)[CH3:37]>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([CH2:9][C:10]([N:12]([N:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22]1)[CH3:13])=[O:11])[C:23]1[CH:28]=[C:27]([C:29]2[O:30][N:38]=[C:36]([CH3:37])[N:31]=2)[CH:26]=[CH:25][C:24]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(N)=O)cc1N(CC(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Reactant: COC(C)(OC)N(C)C
Product: Cc1noc(-c2ccc(C)c(N(CC(=O)OC(C)(C)C)CC(=O)N(C)N3Cc4ccccc4C3)c2)n1
Yield: 75 %

Procedure:
Using the compound (500 mg, 1.11 mmol) of Example 81, step B, and N,N-dimethylacetamide dimethylacetal (2.5 ml), and according to the method of Example 83, step A, the title compound (406 mg, yield 75%) was obtained as a pale-bistered amorphous solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[C:1]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 1 h

Procedure:
Acetyl chloride (0.27 ml) was added to a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.0 g) and triethylamine (0.56 ml) in tetrahydrofuran at 0° C. and the mixture stirred for 1 hour. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(acetyl)oxime (0.83 g)as an orange solid m.p.130-134° C. Compound 10.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:61]([O:63][C:64](=[O:67])[CH2:65][NH2:66])[CH3:62]>CN(C)C=O>[CH2:61]([O:63][C:64](=[O:67])[CH2:65][NH:66][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:2]=2[Cl:1])=[CH:23][CH:22]=1)[CH3:62]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
The solution of 4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoic acid (8.207 g, 18.7 mmol), triethylamine (5.2 mL, 37.4 mmol) and HBTU (8.24 g, 21.7 mmol) in dry dimethyl formamide (150 mL) was stirred at room temperature for five minutes before glycine ethyl ester hydrochloride (Aldrich) (2.614 g, 18.7 mmol) was added. The pH of the reaction mixture was adjusted to 8 by the addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (300 mL), the precipitated crystals were filtered off, washed with water and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and n-hexane:ethyl acetate=2:1 as eluent to yield 7.68 g (78%) of the title compound. MS (EI) 524 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH2:22][CH:23]=[CH2:24])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:22]([N:17]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:20][N:19]([CH2:2][C:3]2[N:4]=[CH:5][NH:6][C:7]=2[CH3:8])[C:18]1=[O:21])[CH:23]=[CH2:24]
Reactant: Cc1[nH]cnc1CO
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2nc[nH]c2C)c1=O
Temperature: 25 °C

Procedure:
100 mg (0.89 mmol) of 4-hydroxymethyl-5-methyl-1H-imidazole, 252 mg (1.07 mmol) of the compound from Example 12A and 370 mg (2.68 mmol) of potassium carbonate were dissolved in 4.5 ml of DMF and 4.5 ml of water, and the mixture was stirred in a microwave oven at 200° C. for 75 min. After cooling to RT, for work-up, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: first cyclohexane/ethyl acetate 1:1, then dichloromethane/methanol 10:1). This gave 153 mg (52% of theory) of the target compound in a purity of 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][C@@H:35]([CH3:39])[NH:34]1>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:29])[CH3:30])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:37]4[CH2:36][C@H:35]([CH3:39])[NH:34][C@H:33]([CH3:32])[CH2:38]4)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3Cl)c2)S1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4Cl)c3)S2)C[C@H](C)N1

Procedure:
5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 2,6-(cis)-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1cccs1
Product: COc1ccc2c(c1)c(C1CCN(Cc3cccc(C(=O)O)c3)CC1)cn2Cc1cccs1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.4 g (7.4 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole (example 89, part C) and 1.9 g (8 mmol) 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 1.4 g (41% of yield) of the expected acid were obtained.
Reaction SMILES: C(N(CC)CC)C.F[B-](F)(F)F.[CH3:13][C:14]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[Se+:18]=1)([CH3:16])[CH3:15].[Cl:28][C:29]1[C:30](=[O:36])[C:31]([Cl:35])([Cl:34])[C:32]=1Cl.[OH-].[Na+]>ClCCl>[CH3:16][C:14]([C:17]1[Se:18][C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:21](=[CH:23][C:32]2[C:31]([Cl:35])([Cl:34])[C:30](=[O:36])[C:29]=2[Cl:28])[CH:22]=1)([CH3:13])[CH3:15]
Reactant: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Reactant: O=C1C(Cl)=C(Cl)C1(Cl)Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)[Se]1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution of triethylamine (14.8 g, 147 mmole) in dichloromethane (40 mL) was added dropwise under nitrogen to a solution of 2,6-bis(1,1-dimethyl-ethyl)-4-methylselenopyrylium tetrafluoroborate (26.2 g, 73.4 mmole, prepared in Examples 1 and 2 above) and 2,3,4,4-tetrachlorocyclobut-2-en-1-one (15.2 g, 73.4 mmole) in dichloromethane (60 mL), contained in a flask equipped with a condenser and an outlet connected to a gas-washing bottle containing 10% aqueous sodium hydroxide solution; the addition was effected at a rate such that the temperature of the reaction mixture did not exceed 35° C. After the addition had been completed, the reaction mixture was stirred for one hour, then applied to a column packed with silica gel. Elution with dichloromethane, followed by evaporation of the solvent under reduced pressure, provided the crude product, which was further purified by trituration with trifluoroethanol for one hour to give 3-[[2,6-bis(1,1-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-2,4,4-trichlorocyclo-but-2-en-1-one (23 g, 71% yield) as maroon crystals. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([NH:30][C:31](=[O:33])[CH3:32])([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=2)[CH:12]1O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(OCC)C>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[C:5]([NH:30][C:31](=[O:33])[CH3:32])([C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=2)[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)=C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
2-Acetylamino-2-(6-octyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-malonic acid diethyl ester (compound A, 755 mg, 1.58 mmol)) is dissolved in acetic anhydride (5 mL) followed at 0° C. by a catalytic amount of ferric chloride (66 mg, 0.4 mmol). The reaction is stirred at 0° C. for an additional 2 hours, and 20 mL of diethyl ether is added. The reaction is carefully poured into 50 mL of ice cold water and the organic layer quickly separated. The organic layer is re-extracted with methylene chloride (2×20 mL) and the combined organic layers were washed once with brine (20 mL) and dried over magnesium sulfate. The organic layer is concentrated under vacuum and the residue is purified by column chromatography (silica gel, 10% ethyl acetate in hexanes) to provide 458 mg of compound B (60%). The complete synthesis is illustrated in FIG. 4.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:30][CH2:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])(=O)=O>CC#N.C(OCC)C>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1oc(-c2ccccc2)nc1CCCOc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 7-hydroxychromane-3-carboxylate (250 mg, 1 mmol) in CH3CN (10 ml), K2CO3 (414 mg) and 3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propyl methanesulfonate (325 mg) were added and the reaction mixture was heated under reflux for overnight. The reaction mixture was cooled to room temperature and diluted with 30 mL of diethyl ether. The diluted solution was passed through a pad of silica and the silica was washed with more ether. The ether solution was evaporated to dryness and purified using silica chromatography. The product was isolated as a white sold (397 mg, 88%).