Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][CH:28]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1cc[n+]([O-])cc1
Yield: 87.5 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.140 g, 0.00040 mol) in dimethoxyethane (7 mL) and water (15 mL) was reacted with 4-phenoxyphenylboronic acid (0.093 g, 0.00043 mol), sodium carbonate (0.105 g, 0.00099 mol) and tetrakis(triphenylphosphine) palladium (0) (0.046 g, 0.00004 mol) at 80° C. for 18 hours. The solid was filtered to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.138 g, 0.00035 mol) as a brown solid. A portion (0.040 g, 0.00010 mol) was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 40% isocratic for five minutes, then 40%-100% acetonitrile—0.1M ammonium acetate over 30 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give the product 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate as a white solid (0.013 g, 0.00003 mol).
Reaction SMILES: Br.Br[CH2:3][C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=O.Br.O=C(C1C2CCN(CC2)C1)C=O.C(=O)(O)O.[NH2:31][NH:32][C:33]([NH2:35])=[NH:34].Cl>O>[NH2:35][C:33]1[N:32]=[N:31][CH:3]=[C:4]([CH:6]2[CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[N:34]=1
Reactant: O=C(CBr)C1CN2CCC1CC2
Reactant: N=C(N)NN
Agent: Br
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: Nc1nncc(C2CN3CCC2CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
(±) 3-(α-Bromoacetyl)-1-azabicyclo [2.2.2 ]octane hydrobromide (EP-0366304, Description 7) (1.0 g, 3.2 mmol) was converted into (±) 2-oxo-2-(1-azabicyclo[2.2.2]octan-3-yl)ethanal hydrobromide using the method described in Example 3. The crude aldehyde was immediately treated with a suspension of aminoguanidine bicarbonate (0.48 g, 3.5 mmol) in water (10 ml), and the solution was acidified to pH4 with 5M hydrochloric acid. The reaction mixture was stirred overnight at room temperature then heated under reflux for 1 h. It was then saturated with potassium carbonate and extracted into chloroform (4×10 ml). The combined organic extracts were dried over sodium sulphate, concentrated in vacuo and the residue chromatographed on neutral alumina in a gradient of 0-8% methanol in chloroform. This afforded the title compound (E6) as a colourless solid (42 mg, 6%) which was converted into the oxalate salt m.p. 175° C. (dec) (from methanol - ether).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[S:19])=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred mixture, prepared by reacting 4.6 g. sodium with 300 ml. dry acetone at room temperature was cooled to 5°C. and 27.3 g. valeramidine hydrochloride was added in one portion. After 20 minutes there was added dropwise during thirty minutes, a solution of 33.8 g. 4-chlorophenyl isothiocyanate in 200 ml. dry acetone while the temperature was maintained at 5° to 10°C. The mixture was stirred for 18 hours at room temperature, filtered and the filtrate was evaporated to dryness under reduced pressure. A solution of the residue in 300 ml. ether was chilled and treated with ethereal hydrogen chloride until acidic and the resulting solid was filtered to give, after recrystallization from acetonitrile 51.1 g. 1-(4-chlorophenyl)-3-(pentanimidoyl)-2-thiourea hydrochloride; m.p. 164°-166°C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:13]=[CH:12][CH:11]=2)(=O)=O.[CH3:26][O:27][C:28]1[CH:34]=[C:33]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)[CH:32]=[CH:31][C:29]=1[NH2:30]>>[CH:18]1([NH:17][C:14]2[C:15]3[C:10](=[CH:9][N:8]=[C:7]([NH:30][C:29]4[CH:31]=[CH:32][C:33]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[CH:34][C:28]=4[O:27][CH3:26])[CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Oc1cc2c(NC3CCCCC3)nccc2cn1)C(F)(F)F
Reactant: COc1cc(-c2cnn(C)c2)ccc1N
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1cc2c(NC3CCCCC3)nccc2cn1

Procedure:
The title compound was prepared according to Method 6 (Example 103) using 5-(cyclohexylamino)-2,6-naphthyridin-3-yl trifluoromethanesulfonate (Preparation 93) and 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19) for 18 hours. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.O>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
0.5 g of 2-chloro-5-nitro-pyridine (3.15 mmol), 1.2 g of tributyl-vinyl-stannane (3.78 mmol), 0.036 g of tetrakistriphenylphosphinpalladium(0) (0.03 mmol), and 0.024 g of triphenylphosphin (0.09 mmol) were dissolved in 20 ml of toluene and stirred for 2 h under reflux. Upon cooling to room temperature, 10 ml of water were added, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (10%). Fractions containing the product were combined, the solvent evaporated to yield 0.528 g of the desired product.
Reaction SMILES: CC(C)(S([NH:6][CH:7]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)C.Cl.O1CCOCC1>CO>[NH2:6][CH:7]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of methyl 5-(1,1-dimethylethylsulfinamido)-5-(2-methoxynaphthalen-1-yl)pentanoate (0.268 g; 0.68 mmol) in MeOH (5 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.35 ml; 1.40 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate. LC-MS (conditions A): tR=0.55 min. and [M+H]+: 288.16 g/mol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Yield: 105.8 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-p-tolylpropan-2-ol (387 mmol, 100 g) was dissolved in carbon tetrachloride (400 mL) and N-bromosuccinimide (387 mmol, 68.9 g) was added in one portion followed by 2,2′-azobis(isobutyronitrile) (0.387 mmol, 0.064 g). The reaction was stirred at reflux for 4 hours, filtered through dicalite and the filtrate was evaporated to leave crude oil. The crude oil was triturated with diethyl ether, the solid obtained was filtered off and the filtrate taken to dryness (3 times) to yield the title compound as an oil (138 g). 1H NMR (CDCl3, 400 MHz): δ 4.49 (2H, s), 7.49 (2H, d), 7.69 (2H, d)
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:9][C:21]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.5 %

Procedure:
Fifteen grams of n-octanol, 7.5 g of 4-(4'-hydroxyphenyl)benzoic acid and 7.0 g of p-toluene-sulfonic acid were dissolved with 100 ml of toluene in a three necked flask with a dehydration, apparatus, and the mixture was refluxed for 15 hours. Water was added to the mixture to separate a toluene layer. Ten grams of 4-(4'-octyloxycarbonylphenyl)phenol (AB) were obtained by removing the toluene layer under reduced pressure followed concentration. (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic acid dispersed in 20 ml of carbon tetrachloride was reacted with 5 ml of thionyl chloride by refluxing for 3 hours. After removing the solvent (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic chloride (AC) was obtained. 1.5 g of (AC) was dissolved with mixed solvent of 80 ml of carbon tetrachloride and 10 ml of pyridine, and then 1.7 g of (AB) was added to the mixed solution with cooling and the mixture was allowed to stand overnight to obtain crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.[CH3:28][SH:29].[Na]>O1CCCC1.C(OCC)(=O)C>[CH3:28][S:29][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: CS
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 77.6 %

Procedure:
A solution of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (1.40 g, 3.55 mmol) and sodium methyl mercaptan (95%, 0.42 g, 5.67 mmol) in tetrahydrofuran (15 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) and recrystallized from hexane/diisopropyl ether to give the title compound (1.12 g, yield 78%) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].N[C:32]1C(C)=CC(C)=CC=1C(=O)CC>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:12][C:5]1[C:4]([C:1](=[O:3])[CH2:2][CH3:32])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[CH3:11])=[O:14])(=[O:21])=[O:22]
Reactant: CCC(=O)c1cc(C)cc(C)c1N
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Product: CCC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that 2′-amino-3′,5′-dimethylpropiophenone was used instead of 2-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[S:9]([C:12]([F:15])([F:13])[F:14])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=S(=O)(Nc1ccc(Br)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ccc(Br)cc2)S(=O)(=O)C(F)(F)F)cc1
Yield: 97.1 %

Procedure:
A suspension of 1.52 g (5 mmol) of N-(4-bromophenyl)-C,C,C-trifluoro-methanesulphonamide (Example 13bv)), 1.56 g (10 mmol) of 4-methoxybenzyl chloride and 1.38 g (10 mmol) of powdered potassium carbonate in 15 ml of acetone was stirred at reflux for 18 hours. Thereafter, the mixture was concentrated and the residue was taken up in 100 ml of water and 100 ml of ethyl acetate, the organic phase was separated and the aqueous phase was extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed neutral with sat. sodium chloride solution, dried over magnesium sulphate and evaporated. The resulting yellow oil was subjected to flash chromatography with hexane/ethyl acetate 95:5. 2.06 g (97%) of N-(4-bromophenyl)-C,C,C-trifluoro-N-(4-methoxy-benzyl)-methanesulphonamide were obtained as a colourless, viscous oil. MS (EI): 423 and 425 (M+, 3%), 121 ([CH2 --C6H4 --OCH3 ]+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][O:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:26]=1[N:40]1[CH2:52][CH2:51][N:43]2[C:44]3[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=3[CH:50]=[C:42]2[C:41]1=[O:53])(=[O:22])[CH3:21].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOCC.O.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[CH2:52][CH2:51][N:43]3[C:44]4[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=4[CH:50]=[C:42]3[C:41]2=[O:53])=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][O:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 90.1 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one 110c (130 mg, 0.4 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (220 mg, 0.5 mmol), DME (4 mL) and 1M aqueous sodium carbonate (1.2 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (23 mg, 0.02 mmol) was added. The mixture was heated in microwave to 130° C. for 20 min. After this time, EtOAc (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-60:35:5 CH2Cl2:Et2O:MeOH to afford a 89% yield (210 mg) of 110d.
Reaction SMILES: [N:1]1([CH2:6]/[C:7](/[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:8]\[C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C>[N:1]1([CH2:6]/[C:7](/[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(/C=C(/COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(COC/C(=C/c2ccc(C(=O)O)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution containing ethyl 4-[3-(1H-imidazol-1-yl)-2-[[(4-methoxyphenyl)methoxy]methyl]-1E-propenyl]benzoate (prepared as in Example 1; 0.7 g, 0.0017 mol) in ethanol (10 ml) was treated with aqueous sodium hydroxide (3.5 ml of 1M). The resulting mixture was stirred at room temperature for 5 hours after which time the solvent was evaporated off under reduced pressure and the resulting residue was dissolved in water (100 ml) and washed with ethyl acetate. The aqueous solution was acidified to pH 6.5 with hydrochloric acid and extracted with ethyl acetate (3×150 ml). The extracts were combined, dried over sodium sulfate, and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was recrystallised from dichloromethane-pentane to yield 4-[3-(1H-imidazol-1-yl)-2-[[(4-methoxyphenyl)methoxy]methyl]-1E-propenyl]benzoic acid as a colourless, crystalline solid, having a melting point of 120°-122° C. and the following structural characteristics:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C@@H:27]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH2:26]2>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[CH2:28][C@@H:27]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH2:26]3)[CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(O)cc2C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)c1cccc(Oc2ccc3c(c2)C[C@H](NS(=O)(=O)C(C)C)C3)c1

Procedure:
To a mixture of the 3-(N-methylsulfamoyl)phenylboronic acid (0.274 mmol, 59 mg), copper (II)acetate (0.137 mmol, 25 mg), triethylamine (0.685 mmol, 96 μL) and 4 Å molecular sieves (100 mg) in DCM (1 mL) was added (R)-N-(5-hydroxy-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.137 mmol, 35 mg) and the resultant mixture stirred at room temperature overnight. The reaction mixture was diluted with DCM (1 mL) before water (0.5 mL) was added and the organic layers separated using hydrophobic frits. The aqueous was extracted with further DCM (1 mL), and the combined organics concentrated using to dryness. The residue was taken up in DMSO and purified by preparative HPLC to give the title compound as a clear film (5.9 mg, 10.1%). MS (ESI): m/z [M−H]− 423.2
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C[N:27]1CCOCC1.N>C1COCC1>[C:9]([O:13][C:14](=[O:15])[NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23](=[O:25])[NH2:27])[CH2:18]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutylchloroformate (2.06 g, 15.0 mmol) was added dropwise with cooling in an ice-methanol bath to a solution of 3-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (3.15 g, 13.0 mmol) and N-methylmorpholine (1.52 g, 15.0 mmol) in THF (40 mL). After stirring for 30 mins, methanolic ammonia (7M, 5 mL) was added. The mixture was allowed to warm to room temperature, and left to stand overnight. The residue remaining on evaporation of solvent was partitioned between aq. NH4Cl (150 mL) and DCM (150 mL). The solid suspended in the organic layer was collected, the filtrate evaporated, and the combined solids crystallised from methanol to afford 2.07 (66%) of (3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester as colourless plates. 1H NMR (400 MHz, MeOD) δ: 6.65-6.59 (m, 1H), 3.40-3.28 (m, 1H), 2.35-2.23, (m, 1H), 2.01-1.92 (m, 1H), 1.91-1.80 (m, 2H), 1.80-1.71 (m, 1H), 1.42 (s, 9H), 1.40-1.21 (m, 3H), 1.19-1.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[CH:5]=[C:6]1[C:11](=[CH:12]2)[CH:10]2[O:19][CH:7]1[C:8](=[CH2:21])[C:9]2=[CH2:20].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>>[CH3:27][O:26][C:22]([CH:23]1[CH2:24][CH2:20][C:9]2[CH:10]3[O:19][CH:7]([C:6]4[C:11]3=[CH:12][C:13]3[C:4](=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][C:14]=3[O:17][CH3:18])[CH:5]=4)[C:8]=2[CH2:21]1)=[O:25]
Reactant: C=C1C(=C)C2OC1c1cc3c(OC)ccc(OC)c3cc12
Reactant: C=CC(=O)OC
Product: COC(=O)C1CCC2=C(C1)C1OC2c2cc3c(OC)ccc(OC)c3cc21

Procedure:
In a manner analogous to that described in Example 1, a mixture of 1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene and methyl acrylate was reacted to give 1,2,3,4,5,12-hexahydro-7,10-dimethoxy-5,12-epoxynaphthacene-2-carboxylic acid methyl ester which was converted via 5,12-diacetoxy-1,2,3,4-tetrahydro-7,10-dimethoxy-2-naphthacenecarboxylic acid methyl ester into 5,12-diacetoxy-1,2,3,4,6,11-hexahydro-7,10-dimethoxy-6,11-dioxo-2-naphthacenecarboxylic acid methyl ester.
Reaction SMILES: C(S(N1CCC2(C(=O)NCC2)CC1)(=O)=O)C(C)C.[CH2:19]([S:23]([N:26]1[CH2:48][CH2:47][C:29]2([C:33](=[O:34])[N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]([OH:46])[C:42](F)([F:44])[F:43])=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH:20]([CH3:22])[CH3:21].BrC1C=CC(C(O)C(F)F)=CC=1>>[F:44][CH:42]([F:43])[CH:41]([C:38]1[CH:37]=[CH:36][C:35]([N:32]2[CH2:31][CH2:30][C:29]3([CH2:47][CH2:48][N:26]([S:23]([CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:24])=[O:25])[CH2:27][CH2:28]3)[C:33]2=[O:34])=[CH:40][CH:39]=1)[OH:46]
Reactant: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(O)C(F)(F)F)cc3)C2=O)CC1
Agent: CC(C)CS(=O)(=O)N1CCC2(CCNC2=O)CC1
Agent: OC(c1ccc(Br)cc1)C(F)F
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(O)C(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(isobutylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one, product of example 167 A) and 1-(4-bromo-phenyl)-2,2-difluoro-ethanol, described in example 176). Light yellow solid. MS (ESI): 431.18 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:7][CH2:6][C:5]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1.Cl>>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4]1
Reactant: CN(C)C1CCC(c2ccccc2)(c2ccc(Cl)cc2)C1
Agent: Cl
Product: CN(C)C1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
1-dimethylamino-3-(4-chlorophenyl)-3-phenylcyclopentane/PUN 123 /Hydrochloride m.p. 168°-170° C.