Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:25])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([CH:23]=[CH2:24])[O:17]1.CCN(CC)CC>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH3:21][C:20]1([CH3:22])[C:16]([CH3:25])([CH3:15])[O:17][B:18](/[CH:23]=[CH:24]/[C:2]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[O:19]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
To a mixture of 4-(4-bromobenzyl)morpholine (4.18 g, 16.3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3 mL, 17.7 mmol, 1.1 eq.) and toluene (30 mL) in a 20 mL microwave vial was added Et3N (4.56 mL, 32.4 mmol, 2 eq.), followed by Pd(PtBu3)2 (83 mg, 0.16 mmol, 1 mol %). The resulting mixture was purged with argon, then capped and heated at 80° C. oil bath for 1 h. After cooling to rt, the reaction was diluted with half saturated NaHCO3 (40 mL) and the product was extracted with EtOAc (2×60 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated in vacuo. Trituration with hexane and sonication provided a solid that was collected by suction filtration (white solid, 2.55 g). After evaporation of the solvent in vacuo, the residue solidified and a second crop of crystals was obtained by suction filtration from a small amount of hexane (pale yellow crystals, 0.22 g). Evaporation of the mother liquor provided a yellow liquid which was purified using Biotage Isolera (20-80% EtOAc in hexane, SNAP-50 g column) to give a third portion of the product (yellow solid, 1.58 g; total yield 4.35 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.0 Hz, 2H), 7.40 (d, J=18.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.16 (d, J=18.0 Hz, 1H), 3.72 (t, J=4.4 Hz, 4H), 3.50 (s, 2H), 2.47-2.42 (m, 4H), 1.32 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 32 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (13 mg, 32%) which was obtained as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33])[CH2:21][CH2:22][CH3:23])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:10][C:11]([F:14])([F:13])[F:12])[CH:4]=2)[C:25]1=[O:33])[CH2:21][CH2:22][CH3:23])[CH3:16]
Reactant: Nc1ccc(CO)cc1OC(F)(F)F
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2ccc(N)c(OC(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Yield: 8.3 %

Procedure:
(4-Amino-3-trifluoromethoxy-phenyl)-methanol (100 mg, 0.48 mmol) and 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (133 mg, 0.48 mmol) is taken up in 4 mL of tetrahydrofuran and then triphenyl phosphine is added (190 mg, 0.72 mmol). The reaction is stirred at room temperature and DIAD (141 μL, 0.72 mmol) is, added dropwise to the reaction. The reaction is stirred at room temperature for 1 hour and then the solvent evaporated in vacuo. Product is purified by preprative HPLC 30%-90% acetonitrile/water to give the title compound (20 mg, 0.04 mmol 9%). LCMS (ESMS): m/z 466.1 (M+H+).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH:2]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:25])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Solvent: CCO
Product: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
18 g of D-glucose are stirred in 50 ml of ethanol at 70° C., 18.5 g of dodecylamine are then added, heating is continued until the solution is clear, the mixture is left to cool to room temperature and the precipitated crystals are filtered off with suction for a further 20 hours. They are washed with ethanol and ether and dried in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14](Br)=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Zn](C)[CH3:19]>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14]([CH3:19])=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Zn]C
Reactant: CCOC(=O)N1CCc2scc(Br)c2C(C)C1
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2scc(C)c2C(C)C1
Temperature: 100 °C

Procedure:
The product of step (a) (150 mg, 0.47 mmol) was dissolved in 3 mL dioxane and treated with Me2Zn (0.47 mL of 2M in toluene) and Pd(ddf)2Cl2 (11 mg, 0.014 mmol). After heating to 100° C. for 3 hours, the reaction was quenched with water and filtered. The filtrate was partitioned between EtOAc and water (7 mL each). The organic layer was dried over MgSO4 and concentrated to give 92 mg of the sub-title compound, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([CH3:27])([CH3:26])[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+]>[Pd].CO>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([C:9]([CH3:27])([CH3:26])[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
20.0 g of 3-phenoxybenzyl 2-(3-chloro-4-hydroxyphenyl)-2-methylpropyl ether prepared in the above step (1), 2.67 g of 95% sodium hydroxide and 1.0 g of 5% Pd-C (50% hydrous) were added to 100 ml of 80% methanol and the mixture was stirred at 100° C. under a hydrogen pressure of 20 to 30 kg/cm2G for 6 h. After cooling, the catalyst was removed by filtration and the catalyst was washed thoroughly with benzene. The solvent was distilled off under reduced pressure. A dilute aqueous hydrochloric acid solution was added to the distillation residue. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure to obtain 18.2 g of intended 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether (m.p. 69.2° to 70.0° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl.ClCCl.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1nc(OCCCC(C)C)c(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(OCCCC(C)C)c(Br)cc1N
Temperature: 25 °C
Yield: 131.6 %

Procedure:
In a 50 ml single-necked round-bottomed flask equipped with a condensor, 1.36 g of crude 3-bromo-6-methyl-2-(4-methyl-pentyloxy)-5-nitro-pyridine is dissolved in 3.15 ml of methanol and the resulting solution stirred. Under cooling using an ice/water bath, 3.15 ml of concentrated aqueous HCl is added dropwise by syringe (precipitation is observed). The ice bath is removed and 2.23 g anhydrous SnCl2 is added in portions. Stirring is continued under heating to reflux for 5.5 h (yellow suspension). After cooling this mixture to ambient temperature, it is concentrated in vacuo to give a yellow solid. After adding dichloromethane, 10 ml of a 4 M aqueous NaOH solution is added (pH 12). After extraction, the organic phase is dried over Na2SO4, filtered and the solvent removed in vacuo to give 1.62 g of a yellow oil. Purification is done by flash chromatography [silica gel cartridge (50 g, 150 ml) of a solid deposition with heptane/ethyl acetate 4:1 (v:v)] to give 490 mg of the compound in the form of a yellow oil. RP HPLC: Retention time of compound: 2.12 minutes.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:15][N:14]([CH3:16])[CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].[CH2:23]([NH:26][C:27](=[O:47])[NH:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[C:31]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=2)[CH:30]=1)[CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>C(COC)OC.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>[CH3:16][N:14]1[CH2:15][CH:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:32]4[CH:33]=[N:34][C:29]([NH:28][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:47])=[CH:30][C:31]=4[C:38]4[S:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[N:42]=4)=[CH:11][CH:10]=3)[C:5](=[O:22])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2)[CH2:13]1
Reactant: CCOC(=O)c1cn(C2CN(C)C2)c2ccc(I)cc2c1=O
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C2CN(C)C2)cn1
Temperature: 30 °C

Procedure:
A suspension of ethyl 6-iodo-1-(1-methylazetidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 31, 500 mg, 1.21 mmol) in dimethoxyethane (9.7 mL) in a vial was stirred with heating to obtain solution. The solution was cooled to 30° C. and trans dichlorobis(triphenylphosphine)palladium (II) (111 mg, 0.16 mmol) was added. The mixture was stirred for ˜10 min at room temperature, then 6-(3-propylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 47, 1.3 eq) was added to the mixture followed by an aqueous solution of sodium bicarbonate (252 mg in 2.4 mL of water) and the vial was sealed. The mixture was stirred at 75° C. for 1 h and then cooled to 0° C. The solid that formed was isolated by filtration, washed with a small amount of dimethoxyethane, then methyl tert-butyl ether to give 735 mg of yellow solid, which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:21])[NH:15]2)[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH3:5].[CH3:22][O-:23].[Na+]>CO>[OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]([O:20][C:22](=[O:23])[C:17]2[CH:18]=[CH:19][C:10]([CH3:2])=[CH:11][CH:16]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:21])[NH:15]2)[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH3:5]
Reactant: C[O-]
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [Na+]
Solvent: CO
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)c2ccc(C)cc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril was dissolved in 150 ml of methanol, and a 15% methanolic solution of sodium methylate was added to the solution in an equimolar amount relative to the starting carbostyryl compound. The mixture was concentrated to dryness and the resulting residue was dissolved in 100 ml of dimethylformamide. 3.0 g of p-toluylic acid chloride was added to the solution while cooling with ice-water, and the resulting mixture was stirred for 1.5 hours at room temperature. The precipitate formed was separated by filtration, and washed successively with dimethylformamide and diethyl ether to obtain 4.2 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxycarbostyril having a melting point of 197°-198° C. (after recrystallization from chloroform-diethyl ether).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]1([C:18]2[S:26][C:25]3[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=4)=[N:23][CH:22]=[N:21][C:20]=3[CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:34][C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:24]3[C:25]4[S:26][C:18]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[CH:19][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:33][CH:32]=2)=[CH:2]1
Reactant: Nc1ccc(Nc2ncnc3cc(-c4ccccc4)sc23)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: c1ccc(-c2cc3ncnc(Nc4ccc(NCc5c[nH]c6ccccc56)cc4)c3s2)cc1

Procedure:
The title compound was prepared from 1H-indole-3-carbaldehyde(12 mg, 0.079 mmol) and N-(6-Phenyl-thieno[3,2-d]pyrimidin-4-yl)-benzene-1,4-diamine (150 mg, 0.471 mmol) by a procedure analogous to example 73. RP18-HPLC RT: 6.932 minutes; API MS: 448.20 (M+1) MP: 259-261° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.[N:13]1([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[O:1]1[C:2]2=[CH:3][CH:4]=[CH:9][C:8]2=[CH:7][CH:6]=[C:5]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:25]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Product: O=C(c1ccccc1-c1ccc2cccc-2o1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 2-Benzofuran boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 52 mg (47%). MS (ES+) 375.2
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[C:4]([Cl:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH2:9][Br:11])=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(F)c(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: Fc1cc(CBr)c(Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of 4-bromo-2-chloro-5-fluorotoluene (997 mg, 4.46 mmol), N-bromosuccinimide (837 mg, 4.70 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (20 mL) was heated to reflux at 85° C. for 18.5 hours under nitrogen. The reaction mixture was concentrated in vacuo to afford a cream solid residue. The residue was suspended in heptane (40 mL), filtered and the filtrate then concentrated in vacuo to afford the title compound a clear oil (1.35 g, 100%). The compound was used without further purification in the next step.
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[N:23]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:22]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1>CN(C=O)C.C(OCC)(=O)C>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:2][CH3:3])[CH:28]=4)[N:23]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:22]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(O)ccc2n1Cc1cccc(OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC)ccc2n1Cc1cccc(OC)c1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
Iodoethane (468 mg, 3.0 mmol) and powdered potassium carbonate (138 mg, 1.0 mmol) was added to a solution of ethyl 3-[4-(cyclopropylmethoxy)phenyl]-5-hydroxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 66, 120 mg, 0.25 mmol) in DMF (5 mL). The mixture was heated (50° C.) for 16 h and then cooled. The resulting mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC using 4:1 ethyl acetate/hexane as the eluant, to afford 52 mg (42%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.42 (d, 1 H), 7.37 (d, 2 H), 7.19 (t, 1 H), 6.92-7.01 (m 4 H), 6.74-6.77 (m, 1 H), 6.64-6.68 (m, 2 H), 5.80 (s, 2 H), 4.13 (q, 2 H), 3.88-3.98 (m, 4 H), 3.69 (s, 3 H), 1.34-1.45 (m, 4 H), 1.04 (t, 3 H), 0.56-0.66 (m, 2 H), 0.34-0.44 (m, 2 H).
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:28])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:18])([F:17])[F:16]>>[Cl:6][C:7]1[CH:8]=[C:9]([O:28][CH2:2][CH:3]([F:5])[F:4])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)([OH:26])[C:15]([F:16])([F:18])[F:17]
Reactant: FC(F)CBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCC(F)F)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromo-1,1-difluoroethane and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=411.0 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]>C1COCC1>[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:33][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Reactant: CCCC1CCC(C2CCC(CCO)CC2)CC1
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCOC(=O)C(F)(F)F)CC2)CC1

Procedure:
Trifluoroacetylbenzotriazole in an amount of 7.0 g (33 mmol) was dissolved in 70 ml of THF, 5.0 g (20 mmol) of 2-(4-(4-propylcyclohexyl)cyclohexyl)ethanol was added thereto, they were refluxed for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=5/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 2.9 g (8.3 mmol) of trifluoroacetic acid 2-(4-(4-propylcyclohexyl)cyclohexyl)-ethyl ester. Yield of this compound based on 2-(4-(4-propylcyclohexyl)cyclohexyl)ethanol was 42%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: OC1CCOCC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2C1CCOCC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and tetrahydro-4-pyranol in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([Br:8])=[CH:6][S:5][N:4]=1.[N+](C1C=C([N+]([O-])=O)C=C(C(OO)=O)C=1)([O-])=[O:10]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([Br:8])=[CH:6][S:5](=[O:10])[N:4]=1
Reactant: O=C(OO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COc1nscc1Br
Solvent: ClCCl
Product: COC1=NS(=O)C=C1Br
Reaction time: 1 h

Procedure:
To a solution of 3-methoxy-4-bromoisothiazole (2.9 g, 15 mmol) in methylene chloride (15 ml) there can be was added, in portions, 3,5-dinitroperbenzoic acid (3.4 g, 15 mmol) with ice bath cooling. After about one hour, the precipitated 3,5-dinitrobenzoic acid can be filtered off and the solvent evaporated in vacuo. By triturating the residue with diethyl ether, a crystalline product, 3-methoxy-4-bromoisothiazole-1-oxide, can be obtained. Additional material can be obtained by chromatographing the mother liquors on silica gel, eluting with chloroform.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.B(F)(F)F>C1C=CC=CC=1.CCOCC>[CH3:9][C:4]1([CH3:8])[CH:3]2[C:2](=[CH2:1])[CH:7]([CH:12]([CH3:13])[CH2:11][C:10]2=[O:14])[CH2:6][CH2:5]1
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=C1C2CCC(C)(C)C1C(=O)CC2C

Procedure:
A solution of 2,6,6-trimethyl-1-crotonoyl-2-cyclohexene (1.0 g.) in a mixture of benzene and ether (10 ml.) was heated at ca. 80° in the presence of a catalytic amount of a saturated solution of BF3 in ether. The course of the reaction was followed by v.p.c. analysis. Three hours were usually necessary for converting the starting material into the bicyclic compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:20][C:21]([OH:23])=[O:22])=[C:3]([O:10][CH2:11][CH3:12])[CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCC(=O)O
Yield: 120.2 %

Procedure:
4-Hydroxy-3-ethoxybenzaldehyde (5.0 g, 36 mmol), potassium carbonate (5.0 g, 36 mmol), and t-butyl bromoacetate (5.9 mL, 36 mmol) were heated to 55° C. overnight in DMF (35 mL). After removal of solvent, the mixture was extracted with EtOAc and water, then brine. After drying (Na2SO4), solvent was removed no yield a white solid (9.7 g). mp 90°-92.6° C. MS(NH3): 298 (base, M+NH4).