Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH:26]1[CH2:28][CH2:27]1)[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH:26]2[CH2:27][CH2:28]2)[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2C1CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.754 ml, 7.71 mmol) is added to (R)-[3-(1-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.390 g, 1.03 mmol) and triethylamine (0.711 ml, 5.13 mmol) in dichloromethane (5 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a yellow solid. HPLC r.t. 4.96 min; MS for C20H24FN3O5 m/z 406 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reaction time: 8 h

Procedure:
62.2 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile are suspended in 0.4 ml of DMF, and 11.4 mg (0.2 mmol) of methyl isocyanate are added at room temperature. The mixture is stirred overnight, filtered and purified by preparative HPLC.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11](C(O)=O)=[C:4]2[N:3]=1>C(=O)([O-])O.[K+]>[CH3:8][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([SH:1])[CH:7]=1
Reactant: Cc1cc(S)nc2c(C(=O)O)cnn12
Agent: O=C([O-])O
Agent: [K+]
Product: Cc1cc(S)nc2ccnn12

Procedure:
2.00 g of 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid were heated to 220° under argon for 1 hour. After cooling, the reaction mixture was taken up in 10 percent potassium hydrogen carbonate solution. The insoluble portion was filtered off under suction and taken up in water. The solution was acidified to pH 2 and the precipitate was filtered off under suction. After drying, there was obtained 7-methylpyrazolo[1,5-a]pyrimidine-5-thiol.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:8](Br)([CH3:11])([CH3:10])[CH3:9]>CCCCC>[C:8]([C:2]1([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:1]=[CH:5][CH:4]=[CH:3]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Product: CC(C)(C)C1(C(C)(C)C)C=CC=C1
Reaction time: 0.75 h

Procedure:
In this example, freshly distilled cyclopentadiene, a 50 wt % aqueous solution of potassium hydroxide, and tertiary-butyl bromide in the molar ratio of 1:40:5 were stirred together in a reactor. The quaternary ammonium halide, Adogen® 464 is added in the amount of one gram per mole of the potassium hydroxide. These reactants were stirred together and heated to 60° for 75 minutes and then at 100° for an additional 45 minutes. During the reaction foaming may occur which should be controlled. The reaction mixture is then cooled, diluted with pentane, washed with water and dried over magnesium sulfate. The pentane is then removed by vacuum. The crude residue contains the product and the Adogen® 464. Chromatography of the crude material over silica gel yielded di(tert-butyl)-cyclopentadiene. The overall calculated yield is 90 wt % based on the starting cyclopentadiene material.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[CH3:15])[CH3:3].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:15][C:6]1[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OC(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1OC(C)C
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrophenyl 1-methylethyl ether (D73) (0.53 mmol, 115 mg) in dimethylformamide (3 mL) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.53 mmol, 106 mg, 1 eq) and diisopropylethylamine (0.53 mmol, 68.5 mg, 1 eq) under argon at room temperature and then heated at 80° C. overnight. The mixture was then concentrated under reduced pressure, then treated with 10% aqueous sodium carbonate solution and extracted with ether/ethyl acetate. The organics were dried, concentrated under reduced pressure and purified by chromatography on silica (ethyl acetate/petrol ether) to give the title compound as a solid (0.2 mmol, 80 mg, 39% yield). M+H 338.1 for main fragment (loss of tert-butyl group).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: O=Cc1cc(O)ccc1-c1ccc(Cl)cc1

Procedure:
2-bromo-5-hydroxybenzaldehyde (20 g), 4-chlorophenylboronic acid (17.1 g) and dichlorobis(triphenylphosphine) palladium(II) (1.75 g) were dissolved in 475 mL of a dimethoxyethane:ethanol:2M Na2CO3 solution (7:2:2). The mixture was heated to reflux for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed thoroughly with water and with brine, dried over MgSO4, filtered and concentrated. The resulting solid was slurried in 500 mL of hexane:ether mixture (2:1). The title compound was collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C.CCCCCC>O1CCCC1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:39])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (50.0 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then a solution of phenylacetyl isocyanate in toluene (0.80 ml, 0.5 M solution in toluene, Production Example 1) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:ethanol=9:1) Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1 ml)-hexane (0,5 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (63.1 mg, 88.1%) as a pale yellow solid.
Reaction SMILES: C[Si](C)(C)CCOC(=O)C1C=CC=CC=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[CH3:25][Si:26]([CH3:52])([CH3:51])[CH2:27][CH2:28][O:29][C:30](=[O:50])[C:31]1[CH:36]=[C:35](Br)[C:34]([Cl:38])=[CH:33][C:32]=1[O:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[CH3:25][Si:26]([CH3:52])([CH3:51])[CH2:27][CH2:28][O:29][C:30](=[O:50])[C:31]1[CH:36]=[C:35]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[C:34]([Cl:38])=[CH:33][C:32]=1[O:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)OCC[Si](C)(C)C
Reactant: CC1(C)OB(c2ccccc2C(=O)OCC[Si](C)(C)C)OC1(C)C
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCC[Si](C)(C)C

Procedure:
2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-benzoic acid-2-trimethylsilanyl-ethyl ester (2.7 g) was similarly prepared according to Step 2D from 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCI): 513.2, 459.1; tR=3.62 min. (method 1)
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2].Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:12][C:10]2[CH:11]=[C:5]3[CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7][N:6]3[N:9]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CCN1CCn2nc(N)cc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 208b (1.0 g, 6.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.6 g, 6.0 mmol), Pd2(dba)3 (274 mg, 0.30 mmol), XantPhos (347 mg, 0.60 mmol), cesium carbonate (3.9 g, 12.0 mmol), and 1,4-dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 208c (630 mg, 29%) as a yellow solid. MS-ESI: [M+H]+ 352
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]2[CH2:45][CH2:44]2)[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH:43]1([N:41]2[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42]2)[CH2:45][CH2:44]1
Reactant: O=c1ccc(Br)cn1C1CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 120 °C
Yield: 73.9 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (0.729 g, 1.52 mmol) in 1,4-dioxane (16 mL) were added 5-bromo-1-cyclopropylpyridin-2(1H)-one (0.323 g, 1.51 mmol), 2 M aq Cs2CO3 (4 mL), and PdCl2(dppf)CH2Cl2 (0.079 g, 0.0964 mmol). The mixture was degassed and heated, under a nitrogen atmosphere, at 120° C. for 16 h. The mixture was diluted with CH2Cl2, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with MeOH/CH2Cl2 to afford 0.543 g (74%) of (S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.41 min, m/z 487 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.66-7.64 (m, 2H), 7.30-7.19 (m, 7H), 6.94 (d, J=8.2 Hz, 2H), 6.52 (d, J=10 Hz, 1H), 5.48 (q, J=7.0 Hz, 1H), 3.32-3.26 (m, 1H), 2.97-2.92 (m, 1H), 2.46-2.32 (m, 2H), 2.16-2.09 (m, 1H), 2.08 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 1.10-1.05 (m, 2H), 0.90-0.86 (m, 5H); 13C NMR (100 MHz, CD3OD) δ 165.59, 155.82, 144.08, 141.05, 139.60, 136.60, 136.30, 129.77, 128.86, 128.64, 126.83, 126.15, 121.93, 120.53, 85.33, 71.67, 55.18, 54.78, 37.46, 34.10, 33.04, 31.79, 30.00, 15.60, 7.49, 7.47.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:10])[C:13]([NH:14][N+:15]([O-:17])=[O:16])=[NH:18])=[CH:4][CH:3]=1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CNCc1ccc(Cl)nc1
Solvent: CCO
Product: CN(Cc1ccc(Cl)nc1)C(=N)N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A mixture of 13.8 g of 6-chloro-N-methyl-3-pyridinemethanamine, 10.8 g of S-methyl-N-nitroisothiourea and 60 ml of ethanol was heated at 50° C. with stirring for 2 hours and then refluxed for additional 5 hours. After cooling, the separated crystal was collected by filtration, washed with a small amount of ethanol, and dried to obtain 14.7 g of the title compound. This compound is No.1 in Table 1. m.p.: 158.0° C. (Decomposed).
Reaction SMILES: [OH:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH3:15])[C:5]=2[CH2:4][CH2:3]1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CC1C=C2C(=CC=1)NC1CCC(OS(C3C=CC(C)=CC=3)(=O)=O)CC2=1>>[CH3:15][N:6]1[C:5]2[CH2:4][CH2:3][CH:2]([O:1][S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c2c(c3ccccc31)CC(O)CC2
Agent: Cc1ccc(S(=O)(=O)OC2CCc3[nH]c4ccc(C)cc4c3C2)cc1
Product: Cc1ccc(S(=O)(=O)OC2CCc3c(c4ccccc4n3C)C2)cc1

Procedure:
The 9-methyl-3-tosyloxy-1,2,3,4-tetrahydrocarbazole was prepared from 49 g. of 3-hydroxy-9-methyl-1,2,3,4-tetrahydrocarbazole and 49 g. of tosyl chloride using the procedure described in Example 21 for the preparation of 6-methyl-3-tosyloxy-1,2,3,4-tetrahydrocarbazole. There was thus obtained 81 g. of 9-methyl-3-tosyloxy-1,2,3,4-tetrahydrocabazole which melted at 155°-157°C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1>C(O)C.[H][H].[Pd]>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCc1cc2ccoc2cn1
Agent: [Pd]
Solvent: CCO
Product: OCc1cc2c(cn1)OCC2
Yield: 99.6 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethanol (1.29 g, 8.7 mmol) was dissolved in ethanol (50 ml) and hydrogenated under 1 atmosphere of hydrogen at room temperature over 10% palladium on carbon for 18 h. The mixture was filtered and the filtrate evaporated to dryness to provide the desired compound (1.31 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[C:12]([O:23][CH3:24])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.Cl.[OH-].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[C:12]([O:23][CH3:24])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(OCc3ccccc3)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(OC)c(O)cc2o1

Procedure:
6-Benzyloxy-5-methoxybenzofuran-2-carboxylic acid ethyl ester (7.3 g), acetic acid (45 ml) and conc. HCl (24 ml) were stirred at 50° C. for 0.5 hour. Water was added and pH adjusted to 3 with NaOH. The mixture was extracted with ethyl acetate. Ethyl acetate was dried with Na2SO4 and evaporated to dryness. The product was recrystallized from toluene.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:23][C:20]2[CH:21]=[N:22][C:17]([C:16]([F:25])([F:15])[F:24])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Product: FC(F)(F)c1ccc(CCNc2ccc(C(F)(F)F)nc2)cc1

Procedure:
In analogy to example 33, step 1, (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with 6-trifluoromethyl-pyridin-3-ylamine (commercially available) to give the title compound MS m/e: 335.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:19]([O-])=O)=[CH:7]1)[CH3:2]>CC(O)=O.O.[Fe]>[O:17]=[C:16]1[CH2:15][C:10]2[C:9]3=[C:14]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH:7]=[C:8]3[NH:19]1)[CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)O)cccc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1cc2c3c(cccc31)CC(=O)N2
Temperature: 80 °C

Procedure:
To a solution of [1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetic acid from Step F (250 mg, 0.816 mmol) in AcOH (18 mL) and H2O (2 mL) was added iron powder (456 mg, 8.16 mmol) and the reaction mixture was heated at 80° C. for 18 h. The mixture was concentrated in vacuo to remove most of the solvent and the residue was partitioned between saturated aqueous NaHCO3 (5 mL) and EtOAc (25 mL). The organic layer was washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=259 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][O:19]C)[N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:21])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: COCc1nccc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CCN(c2ccnc(CO)n2)CC1
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
11.0 g (35 mmol) of 4-[4-(N,N-dimethylsulfamoyl)piperazino]-2-methyloxymethylpyrimidine (Example 1) are dissolved in 45 ml of dry methylene chloride. Between 0° C. and +5° C., 13.2 g (52.5 mmol) of boron tribromide dissolved in 25 ml of methylene chloride are slowly added dropwise under argon. The mixture is stirred for a further 1.5 h while cooling in ice and is hydrolyzed with cold 2 N sodium hydroxide solution. The organic phase is separated off, and the aqueous phase is extracted 3 times more with methylene chloride. The combined organic phases are washed with saturated ammonium chloride solution, water and saturated sodium chloride solution and dried over sodium sulfate and the solvent is removed in vacuo. Crystallization of the residue in butyl acetate results in 7.60 g of solid product of melting point 148°-149° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:26][CH:25]=1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc(OC(F)(F)F)cc2)c1
Yield: 44.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (208 mg, yield: 44.8%).
Reaction SMILES: C[O:2][C:3]1[C:8](=[O:9])[CH:7]=[C:6]([O:10]C)[C:5](=[O:12])[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:19](=[O:29])[C:20]([O:27]C)=[CH:21][C:22](=[O:26])[C:23]=1[O:24]C.[OH-].[Na+].Cl>CO>[OH:29][C:19]1[C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23](=[O:24])[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]1[C:3](=[O:2])[C:8]([OH:9])=[CH:7][C:6](=[O:10])[C:5]=1[OH:12]
Reactant: COC1=CC(=O)C(OC)=C(CCCCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C=C(O)C(=O)C(CCCCCC2=C(O)C(=O)C=C(O)C2=O)=C1O
Temperature: 90 °C

Procedure:
Milligrams of 2,2'-pentamethylenebis(3,6-dimethoxy-1,4-benzoquinone) dissolved in 7 ml of methanol, was treated with 2N-sodium hydroxide, and then warmed at about 90° C. for 30 minutes. After cooling, the solution was adjusted to pH 3 with 6N-hydrochloric acid, and extracted with the mixed solvent of 150 ml of ethyl acetate-ethyl ether (1:1). The organic layer was washed twice with water and twice with an aqueous solution saturated with sodium chloride, and concentrated under reduced pressure to give 203 mg of 2,2'-pentamethylenebis(3,6-dihydroxy-1,4-benzoquinone). Yellow powdery substance.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.C([Li])CCC.CN([CH:37]=[O:38])C>C1COCC1>[CH:37]([C:9]1[C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cn1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2)cc1C=O
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
A solution of 1C (2.40 g, 8.88 mmol) in dry THF (35 mL) and TMEDA (3.35 mL, 22.2 mmol) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 8.9 mL, 22.2 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional 15 min and then at −20° C. for 1.5 h. The reaction was cooled again to −72° C., and dry DMF (1.4 mL, 17.8 mmol) was added while the temperature was maintained below −65° C. The mixture was allowed to stir at RT for 30 min. After this time, no starting material was detected by LC-MS. The solution was cooled to 0° C. and quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 15 min, extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-100%) in hexane to give the title compound as a yellow solid (1.1 g, 42%). LC/MS (method A): retention time=3.43 min, (M+H−tBu)+=243.