Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:35])([F:34])[F:33])[N:16]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:21]([C:20]1[C:15]([NH:14][CH2:13][C@H:10]2[CH2:9][CH2:8][C@H:7]([NH:6][CH2:2][C:3]([NH2:5])=[O:4])[CH2:12][CH2:11]2)=[N:16][C:17]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][C:32]([F:33])([F:34])[F:35])=[N:18][CH:19]=1)#[N:22]
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N)CC1
Reactant: NC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NCC(N)=O)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 2-bromoacetamide (30 mg, 0.21 mmol), 4-{[(trans-4-aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidine-5-carbonitrile (117 mg, 0.28 mmol) and DIPEA (74 mL, 0.43 mmol) in DMF (1 mL) was stirred at 50° C. for 4 h. The reaction mixture was then diluted with EtOAc (30 mL) and washed with water (3×3 mL) and brine. The organic phase was dried over Na2SO4 and concentrated. Silica gel preparative TLC of the crude product using 10:1:0.05 CH2Cl2:MeOH:NH4OH as an eluent afforded 28 mg (27%) of the title compound as a white solid, m/z 476.5 [M−1]+
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[CH2:24](O)[CH:25]=[CH2:26].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+]>C(Cl)Cl.O>[C@@H:6]1([O:8][C@@H:9]2[C@@H:10]([CH2:18][OH:19])[O:11][CH:12]([O:17][CH2:26][CH:25]=[CH2:24])[C@H:13]([OH:16])[C@H:14]2[OH:15])[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]1[OH:20]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=CCO
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
α-D-cellobiose octacetate (48.59 g, 71.6 mmol) was dissolved in methylene chloride (600 mL), and allyl alcohol (29 mL, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (200 mL). After the extract was washed with saturated brine (100 mL) and dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (300 mL) and sodium methoxide (28 mL, 0.14 mol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 2 hours. After Dowex 50w×8 was added thereto until the reaction mixture became neutral and it was filtered, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 8:2:1, V/V) to obtain the desired title compound (24.8 g, yield 91%) as pale yellow amorphous matter.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Br:36][C:37]1[N:38]=[C:39]([C:42](Cl)=[O:43])[S:40][CH:41]=1.BrC1N=C(C(O)=O)SC=1>>[Br:36][C:37]1[N:38]=[C:39]([C:42]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][N:7]=2)=[O:43])[S:40][CH:41]=1
Reactant: O=C(Cl)c1nc(Br)cs1
Reactant: COc1cc2c(Oc3ccc(N)nc3)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)c1nc(Br)cs1
Product: COc1cc2c(Oc3ccc(NC(=O)c4nc(Br)cs4)nc3)ccnc2cc1OCC1CCNCC1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X15 was prepared from tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate and 4-bromothiazole-2-carbonyl chloride, which was prepared similar to Preparative Example 16 step 4 from commercially available 4-bromothiazole-2-carboxylic acid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.53 (m, 2H), 1.98 (d, J=12.5 Hz, 2H), 2.18 (m, 1H), 2.95 (m, 2H), 3.33 (m, 2H), 3.94 (s, 3H), 4.08 (d, J=6.3 Hz, 2H), 6.58 (d, J=5.2 Hz, 1H), 7.45 (s, 1H), 7.54 (m, 1H), 7.87 (dd, J=2.9 Hz, J=9.0 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.31 (s, 1H), 8.45 (d, J=2.9 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 10.61 (br s, 1H). MS (ES) C25H24BrN5O4S requires: 570. Found: 570/572 (M−1-H)+.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[NH:10][CH:9]=1)=[O:7])C>O.CCO>[CH:14]([C:11]1[NH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH3:13])=[O:15]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c[nH]c1C=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
KOH (5 g, 2 eq) was added to a suspension of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.13 g, 44.8 mmol) in water (100 mL) and EtOH (50 mL) with stirring. The mixture was heated to reflux for 2.5 hr, cooled to rt, concentrated to about 2/3 volume, diluted with water (300 mL) and acidified to pH=3 using 1N HCl. The white solid was collected by filtration and dried to afford 6 g (87%) of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid as a tan solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([F:16])=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[C:12]([F:15])[C:13]=1[F:14].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>O.CC(C)=O>[CH3:17][O:1][C:2]1[C:3]([F:16])=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[C:12]([F:15])[C:13]=1[F:14]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)c2c(F)c(O)c(F)c(F)c2C1=O
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: COc1c(F)c(F)c2c(c1F)C(=O)N(C)C2=O

Procedure:
The solids from Example 1 were combined with 375 mL of acetone, and 61.08 g of potassium carbonate. With stirring, 55.77 g of dimethyl sulfate was added, and the entire mixture was heated to reflux for 1.5 h. After cooling, 500 mL of water was added and the reaction was acidified with HCl to a pH of 1.0. The mixture was extracted with ethyl acetate and washed with water. After drying with magnesium sulfate and removal of the solvent, 45.08 g of a yellow solid was collected. The solid was assayed as 72% 4-methoxy-3,5,6-trifluoro-N-methylphthalimide. 19F NMR (ppm acetone d6): -133.0 (m), -140.8 (m), -142.6 (m), 1H NMR (ppm acetone d6) 3.05 (s), 4.19 (s).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C)C1C=CN=CC=1.ClCCl>[C:21]12([C:31]([O:13][CH:10]3[CH2:11][O:12][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][CH2:9]3)=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: OC1COC(c2ccccc2)OC1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC1COC(c2ccccc2)OC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 80 %

Procedure:
1.00 g (5.55 mmol) of 2-phenyl[1.3]dioxan-5-ol, 1.16 ml (8.32 mmol) of triethylamine and 68 mg (0.56 mmol) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and then further for 15 hours at room temperature. Dichloromethane was distilled off under reduced pressure, and to the residue was added aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 1.52 g of the title compound as a pale yellow powder (yield: 80%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].O.CO>C1COCC1>[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=3)[C:20]3[N:21]=[CH:22][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:24][N:25]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH2:7][CH2:6]1)([OH:4])=[O:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)O[C@H]1CC[C@H](C(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid trans-4-methoxycarbonyl-1-cyclohexyl ester (0.101 mmol; 69 mg) and lithium hydroxide monohydrate (0.381 mmol; 16 mg) are dissolved in THF (1 mL), water (0.5 mL) and MeOH (0.1 mL). The solution is stirred for 3 hours at room temperature. The reaction mixture is quenched with aqueous 1M HCl (0.95 mL) and stirred for 15 minutes. To the mixture is added dichloromethane and the organic layer is separated and then concentrated under reduced pressure. The desired product, (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-carboxy-cyclohexyl ester, is obtained in 90% yield (60 mg); ESI-MS m/z: 669 [M+1]+, Retention time 2.13 min (condition A).
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[CH3:13][C:14](=[CH:19][CH2:20][CH2:21][C:22]([CH:24]=[CH2:25])=[CH2:23])[CH2:15][CH2:16][CH:17]=O.C(O)(=O)C(O)=[O:28]>CCCCCC.O.CCOCC>[CH3:13]/[C:14](/[CH2:15][CH2:16]/[CH:17]=[C:10](/[CH:11]=[O:28])\[CH3:12])=[CH:19]\[CH2:20][CH2:21][C:22]([CH:24]=[CH2:25])=[CH2:23]
Reactant: C=CC(=C)CCC=C(C)CCC=O
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: C=CC(=C)CC/C=C(\C)CC/C=C(\C)C=O
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution containing 600 ml. of absolute ether and 640 g. (1.5 moles) of butyl lithium in the form of a 15% solution in hexane was cooled to -10°. In the course of one hour, a solution of 128 g. of diisopropylamine (1.265 moles) in 600 ml. of absolute ether was added with stirring and under nitrogen, then the temperature was allowed to rise to 0°, and stirring was continued for an additional 1/2 hour. The solution was again cooled to -10° and a solution containing 208 g. of propylidene-cyclohexylimine (1.5 moles, b.p. 56°-58°/15 Torr) in 600 ml. of ether was added dropwise over a period of one hour. The mixture was stirred for one hour at 0°, then cooled to -65°, there was then added thereto, within a period of 1/2 hour, 225 g. of 4-methyl-8-vinyl-4,8-nonadienal (1.265 moles) dissolved in 600 ml. of ether, while maintaining the temperature between -66° and -62°. The temperature was allowed to come back to 25° in the course of one hour. The reaction mixture was then poured into 8 1. of water at 0° that contained 600 g. of oxalic acid, under stirring. The organic layer was separated and the aqueous phase extracted twice with ether (2 1.). The extracts were washed with aqueous 5% bicarbonate and with water. After drying and evaporation a yield of 70% of crude β-sinensal was obtained. B.p. 100°-111°/0.04 Torr. An analytical sample was prepared by chromatography on silica with a 3% solution of ethyl acetate in hexane (v/v) as the eluent; b.p. 88°-89°/0.02 Torr. Spectral measurements: IR (CHCl3): 3090, 2710, 1800, 1680, 1640, 1590, 995, 905 cm-1, UV (EtOH): 2260 A (ε= 34,000). NMR (CCl4): 9.33 ppm (1 H, s), 6.37 ppm ( 1 H, t, J = 6 cps), 6.30 ppm (1 H, d of d, J = 17 and 10 cps), 4.8 - 5.4 ppm (5 H, m), 1.9 - 2.6 ppm (8 H, m), 1.69 ppm (3 H, s broad), 1.61 ppm (3 H, s broad).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:10]([OH:18])=[C:9]([O:19][CH3:20])[C:8]=1[O:21][CH3:22])(=[O:5])[CH3:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:3]([O:6][C:7]1[C:8]([O:21][CH3:22])=[C:9]([O:19][CH3:20])[C:10]2[O:18][C:15]([CH2:17][Br:1])([CH3:16])[CH2:14][C:11]=2[C:12]=1[CH3:13])(=[O:5])[CH3:4]
Reactant: C=C(C)Cc1c(C)c(OC(C)=O)c(OC)c(OC)c1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CBr)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Bromine (1.9 g) was added to a solution (40 ml) of 4-acetoxy-2,3-dimethoxy-5-methyl-6-(2-methyl-2-propenyl)phenol (3.0 g) and sodium acetate (1.0 g) in acetic acid, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=85:15 to 4:1) to obtain the title compound (2.5 g, 65%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:42])([C:29]2[N:30](COCC[Si](C)(C)C)[CH:31]=[CH:32][N:33]=2)[CH2:27][CH3:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:42])([C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)[CH2:27][CH3:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCC(O)(c1cc(F)cc(OCc2ccc3c(-c4ccoc4)cc(=O)oc3c2)c1)c1nccn1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(c1cc(F)cc(OCc2ccc3c(-c4ccoc4)cc(=O)oc3c2)c1)c1ncc[nH]1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under N2 the compound from Step 1 (94 mg, 0.159 mmol) was dissolved in THF (2 mL). Tetrabutylammonium fluoride was added ((795 μL, 0.795 mmol) and the reaction was stirred at 55° C. for 1 h. Ethyl acetate was added and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to give an oil which was purified by a flash silica column using EtOAc then 5% MeOH in CH2Cl2 as the eluent. The title compound was obtained: 12.8 mg (17%). Mass spec.: 461 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CCOCC>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:21][C:22](=[O:24])[CH3:23])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC2(CC1)c1ccccc1Oc1c(N)cccc12
Solvent: CCOCC
Product: CC(=O)Nc1cccc2c1Oc1ccccc1C21CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1'-methyl-4-aminoxanthene-9-spiro-4'-piperidine (0.06 g.) and acetic anhydride (0.5 ml.) in ether (20 ml.) is stirred at room temperature for 0.5 hour. The ether solution is washed with saturated sodium carbonate solution and water, dried with MgSO4 and the ether evaporated to give a gummy residue. The residue is crystallised from hexane to give 1'-methyl-4-acetamidoxanthene-9-spiro-4'-piperidine, m.p. 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[C:45]([O:50][CH3:51])[CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[C:45]([O:50][CH3:51])[CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(NC2CCCc3c(OC)cccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2c(OC)cccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.33, 7.23, 7.07, 6.81, 5.50, 4.68, 3.89, 2.87-2.80, 2.72-2.61, 2.12-2.01, 1.91, 1.30-1.19; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1627.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:9]1[C:10]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=2)=[N:11][C:12]([C:15]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:9]1[C:10]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=2)=[N:11][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)=[CH:13][N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CC(=O)CCC3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCCC(=O)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
To a solution of tert-butyl 4-(3-(bis(tert-butoxycarbonyl)amino)-6-(3-oxocyclohex-1-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate (3 g, 5.14 mmol) in MeOH (15 mL) and DCM (10 mL) at RT was added Pd—C (10%, degauss, 1.094 g, 1.028 mmol). The resultant mixture was flushed with hydrogen for 10 min, then stirred at RT for 5 hours under hydrogen atmosphere. The suspension was filtered and the solution was concentrated. ISCO silica column separation (80 g silica, 30 min, 5 to 60% EtOAc in Heptane) afforded the desired product as a light yellow sticky liquid, which solidified upon standing over night. (1.485 g, 2.54 mmol, 49.3% yield). LC-MS (m/z): (MH+) 586.3, 1.17 min.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])(=[O:19])=[O:18].[F:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:36]3[CH:38]=[CH:39][C:33]([O:32][C:31]([F:30])([F:40])[F:41])=[CH:34][CH:35]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:28])=[O:27])(=[O:19])=[O:18]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
White solid. MS (ESI): 533.10 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methanesulfonyl-benzenesulfonyl chloride and 4-(trifluoromethoxy)-aniline.
Reaction SMILES: C([NH:4][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1)(=O)C.[OH-].[Na+].C(O)COCCO>O>[NH2:4][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1
Reactant: CC(=O)NC12CCCC(C1)C1CCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: NC12CCCC(C1)C1CCC2C1
Reaction time: 15.5 h
Yield: 90.3 %

Procedure:
A solution comprising a mixture of 13.0 g (63 millimoles) of 1-acetylaminotricyclo [4.3.1.12,5 ] undecane of formula (II), 8.4 g (210 millimoles) of sodium hydroxide and 160 ml of diethylene glycol is refluxed under stirring for 15.5 hours. After allowing the solution to cool, the reaction solution is poured into water and is extracted with 200 ml of diethyl ether. The ether solution is washed with water and dried with anhydrous sodium sulfate. The ether is distilled out and the resulting residue is subjected to fractional distillation under reduced pressure to collect a fraction having a boiling point of 65°-66° C/1.0 mmHg. Thus 9.40 g (yield: 90.4%) of 1-aminotricyclo [4.3.1.12,5 ] undecane are obtained. After allowing the product to cool, white crystals of a melting point of 111°-113° C are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[C:6]([O:13][C:14](=[O:16])[CH3:15])=[C:5]([CH3:17])[C:4]=1[CH3:18].[H][H]>C(O)C.C(OCC)(=O)C.[Pt]=O>[C:14]([O:13][C:6]1[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]([NH:2][CH3:1])=[C:8]([NH2:9])[C:7]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 55.7 %

Procedure:
A solution of 2.65 g of N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline [prepared as described in step (i) above] in a mixture of 20 ml ethanol and 20 ml of ethyl acetate was shaken at room temperature for 3.5 hours and then at 40° C. for 3 hours in an atmosphere of hydrogen and in the presence of 0.2 g of platinum oxide. At the end of this time, the reaction mixture was filtered to remove the platinum oxide and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.3 g of title compound, melting at 113-116° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 5-(5-bromo-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (139) (13 mg, 0.044 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (38 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(5-bromo(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (141) (11 mg, yield: 64.9%, purity>90%) as white solid.