Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([OH:12])[CH:10]([N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:20])[CH:8]=2)[CH2:3]1.[CH:22](O)=[O:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[CH:11]([OH:12])[CH:10]([N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:20][CH:22]=[O:23])[CH:8]=2)[CH2:3]1
Reactant: O=CO
Reactant: CC1(C)Cc2ccc(N)cc2C(n2ccccc2=O)C1O
Solvent: c1ccncc1
Product: CC1(C)Cc2ccc(NC=O)cc2C(n2ccccc2=O)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-1,2,3,4-tetrahydro-3-naphthol in 15 ml of formic acid and 1 ml of pyridine is boiled for 16 hours and evaporated. Working up in the customary manner gives 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-formamido-1,2,3,4-tetrahydro-3-naphthol.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:12][CH:11]=1>[Pt].CC(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: Nc1ccccc1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
In a 20 ml autoclave were placed 1 g of xylene, 6 mg of a Pt/C catalyst (containing 1% by weight of Pt with respect to the weight of carbon) and 0.25 g (1 mmol) of 4′-chloro-2-nitrobiphenyl obtained in example 1.4. The mixture was stirred under hydrogen pressure (7-8 bar) at 100° C. until the starting material had disappeared (monitoring via HPLC). After completion of the reaction the mixture was cooled to ambient temperature and diluted with 15 ml of acetone. The catalyst was filtered off and the filtrate was evaporated in vacuo yielding 0.2 g (91% of theory) of the title compound in a purity of 93% (HPLC % by weight).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.N1C(C)=CC=CC=1C.CC([OH:26])(C)C.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:7]([CH:8]=[O:26])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: C=Cc1cnc(NC(C)=O)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: CC(=O)Nc1cc(Cl)c(C=O)cn1
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a stirred solution of N-(4-chloro-5-vinylpyridin-2-yl)acetamide (6 g, 30.5 mmol) and 2,6-lutidine (7.11 mL, 61.0 mmol) in a mixture of dioxane (110 mL) and water (25 mL) at 0° C. was added osmium tetroxide, 2.5 wt % solution in 2-methyl-2-propanol (9.58 mL, 30.5 mmol) followed by the addition of sodium periodate (19.58 g, 92 mmol) and the reaction was stirred for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine solution, dried over sodium sulphate, concentrated under reduced pressure. The residue was purified by silica column using hexane/Ethyl acetate to yield N-(4-chloro-5-formylpyridin-2-yl)acetamide as an off-white solid (5.8 g, 28.1 mmol, 92% yield). LCMS (ESI) m/e 197.0 [(M)−, calcd for C8H6ClN2O2197.04] LC/MS retention time (method A): tR=1.21 min; 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.18 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 2.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].N>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][N+:14]([O-:16])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
357.5 g of 2-chloropyridin-4-amine were added in portions to 2.28 l of cold concentrated sulfuric acid. 0.86 l of nitric acid (90%) were slowly added so that the temperature of the reaction mixture always stays below 10° C. After the addition the mixture was stirred for one hour at room temperature and poured into 4 l of water containing 10 kg of ice. 6.2125% (w/v) aqueous NH3 solution were slowly added. The resulting precipitate was filtered, washed with ice water and dried under vacuum to give 316.6 g of the 2-chloro-N-nitropyridin-4-amine. 316.2 g of this intermediate compound were treated with 2.35 l concentrated sulfuric acid and stirred for 30 minutes at 88-94° C. The mixture was cooled to room temperature and poured into 2 l of water containing 5 kg ice. 6.5 l 25% (w/v) aqueous NH3 solution were slowly added. The resulting precipitate was filtered and pre-dried under reduced pressure. Finally the residue was dried by azeotropic distillation with benzene. After crystallization from benzene the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH3:34][N:35]([CH2:37][CH2:38]Cl)[CH3:36]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: CN(C)CCCl
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-dimethylamino)ethyl chloride essentially as previously described. mp 151° C., NMR, IR, MS 529.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])OC(C)(C)C.ClCCl.[NH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>O>[C:15]([O:14][C:8]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1

Procedure:
2.7 ml (20.0 mmol) of triethylamine, 1.84 g (8.45 mmol) of di-t-butyl carbonate and 30 ml of dichloromethane were added to 1.0 g (5.0 mmol) of 4-piperidone, and the resultant mixture was stirred for 19 hours. The reaction solution was diluted with water. After the extraction with dichloromethane, the organic layer was washed with 1 N aqueous hydrochloric acid solution and then with a saturated Aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1-t-butoxycarbonyl-4-piperidone. Separately, 80 ml of tetrahydrofuran and methyl 4-(diethoxyphosphorylmethyl)benzoate were added to 241 mg (6.0 mmol) of sodium hydride under cooling with ice, and the resultant mixture was stirred for 30 minutes and then at room temperature for 30 minutes. Crude 1-t-butoxycarbonyl-4-piperidone obtained as described above was added to the mixture, and they were stirred for 20 hours. The reaction solution was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water and then with a saturated Aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O.C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N=Nc2ccc(OCCCCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
6.47 g (0.018 mol) of ethyl 5-[4-(4-cyanophenylazo)phenoxy]-pentanoate was dissolved in a mixture of 130 mL of dimethylformamide and 41 mL of water in a 500 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 3.9 g (0.098 mol) of NaOH was added through the condenser. Stirring and heating were continued for 1 h after which the reaction mixture was left for cooling to room temperature. The reaction mixture was then diluted with 200 mL of water and acidified with 5.5 N HCl until pH 1.5. The precipitated crude orange product was isolated by filtration. The precipitate was dissolved in 90 mL of hot ethanol and left overnight. After filtration and vacuum drying for 22 h at 50° C. 4.61 g (yield 7.9%) of 5-[4-(4-cyanophenylazo)phenoxy]-pentanoic acid was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:15][C:14]2=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CSc1cc2c(cn1)[nH]c1ccccc12
Solvent: O
Product: CSc1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12

Procedure:
970 mg of 3-methylthio-β-carboline are stirred for 4 hours at room temperature with 60 ml of 65% nitric acid. After introduction of the preparation into water, it is suctioned off and dried. 950 mg of 6-nitro-3-methylthio-β-carboline with a >250° C. melting point are obtained.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C@@H:12]1[N:17]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:16][CH2:15][C:14]([C:24]2[N:25]=[C:26]([SH:29])[S:27][CH:28]=2)=[CH:13]1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:21]([O:20][C:18]([N:17]1[C@@H:12]([CH3:11])[CH:13]=[C:14]([C:24]2[N:25]=[C:26]([S:29][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:27][CH:28]=2)[CH2:15][CH2:16]1)=[O:19])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CCC(c2csc(S)n2)=C[C@@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of lithium hexamethyldisilazide in THE (1M, 1.26 ml, 1.26 mmol) was added at 0° C. to a solution of allyl (6S)-6-methyl-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2H)-pyridine carboxylate (373 mg, 1.26 mmol) in THF (15 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.80 g, 2.52 mmol) and the solution was allowed to stand in a refrigerator for 60 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (590 mg, 76%).
Reaction SMILES: [N:1]([CH:4]1[C:10](=O)[N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1)=[N+]=[N-]>C(O)C.C1COCC1.[Pd]>[NH2:1][C:4]1[N:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[N:9]([CH2:12][C:13]([F:16])([F:14])[F:15])[CH:10]=1
Reactant: [N-]=[N+]=NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1=CN(CC(F)(F)F)c2ccccc2C(c2ccccc2)=N1
Yield: 75.6 %

Procedure:
To a stirring solution of 3-Azido-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine (83.4 mmol ,30 g) in 300 mL ethanol and 150 mL THF was added 10% Pd/C (10 wt %, 3.0 g). Hydrogen gas was bubbled through the solution for 8 h. The reaction was filtered and evaporated under reduced pressure. The residue was crystallized from ethyl ether to give 20.0 g of white crystals. Another 4 g was recovered from evaporation and recrystallization of the filtrates. Combined yield, 86.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)nc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)nc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.24 g) as starting materials, N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in ether, and 4 mol/L-hydrochloric acid/dioxane (0.30 mL) was added. The solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ hydrate (0.43 g). melting point: 158-160° C.
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[C:16]([CH2:26][OH:27])[C:15]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=2)=[O:29])=[CH:14][N:13]=1)=[O:11])C1C=CC=CC=1>[Pd].CO>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[CH2:31][NH:30][C:28]([C:15]1[C:16]([CH2:26][OH:27])=[C:17]([OH:18])[C:12]([C:10]([NH:9][OH:8])=[O:11])=[N:13][CH:14]=1)=[O:29]
Reactant: O=C(NCc1ccc(F)c(Cl)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cnc(C(=O)NO)c(O)c1CO
Yield: 12.3 %

Procedure:
The product of example 13 (0.03 g, 0.330 mmol,) and 10% Pd/C catalyst (25 mg) were stirred in methanol (4.0 mL) under an atmosphere of hydrogen for 1 hour. The catalyst was filtered and the reaction mixture was concentrated under vacuum yielding 0.015 g of N5-(3-chloro-4-fluorobenzyl)-N2,3-dihydroxy-4-(hydroxymethyl)pyridine-2,5-dicarboxamide as a white solid; 1H-NMR (400 MHz, dmso): δ=13.01 (s, 1H), 12.0 (s, 1H), 9.51 (s 1H), 9.02 (t 1H), 8.11 (s, 1H), 7.60 (d 1H), 7.40 (m, 2H), 4.68 (s, 2H), 4.48 (s, 2H); MS-ESI m/z 370 [MH]+.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][O:12]P(O)(O)=O)[C@@H:8]([OH:17])[C@H:7]2[OH:18])[C:4]([NH2:19])=[C:3]([C:20]([NH2:22])=[O:21])[N:2]=1.[N:23]([O-])=O.[Na+].N>C(O)C>[C@@H:6]1([N:5]2[C:4]3[N:19]=[N:23][NH:22][C:20](=[O:21])[C:3]=3[N:2]=[CH:1]2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:17])[C@H:7]1[OH:18]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c1N
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]nnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
The AICAR [for preparation see Synthesis, 2003. No 17, 2639] (1 g, 3.87 mmol) was added to a solution of chlorhydrique acid 6N (25 mL) at −30° C. A solution of sodium nitrite 3M (4 ml, 11.62 mmol) was added and the mixture was stirred at −30° for 2 hours. A pre-cooled (−30° C.) solution of ethanol (25 mL) was added. A solution of ammonia (28%) was added at −20° C. to pH=7. The reaction mixture was evaporated to dryness. The crude product was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (0.81 gr) as a white powder.
Reaction SMILES: BrBr.[CH2:3]([Sn:6](C)([CH3:28])[CH2:7][CH2:8][C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])C=C>CCOCC>[CH3:28][SnH:6]([CH3:3])[CH2:7][CH2:8][C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15]
Reactant: C=CC[Sn](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: BrBr
Solvent: CCOCC
Product: C[SnH](C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Br2 (0.43 g, 2.68 mmol) was added to a solution of 2a (1.20 g, 2.23 mmol) in dry ether (10 mL) at 0° C. The brown reaction mixture was further stirred at room temperature for 1.5 h. After evaporation of solvent, the residue was partitioned between CH2Cl2 and FC-72. The CH2Cl2 phase was further washed with FC-72 for three times. The crude tin bromide 3a was dissolved in dry ether (10 mL) and cooled to −78° C., to which LAH (2.1 mL, 1.0 M in ether) was added. The reaction was quenched with water after stirring at −78° C. for three hours. The crude mixture was further purified by column chromatography with heptane to give 4a as a clear oil (0.72 g, 65% for two steps). 1H NMR (C6D6) δ 4.75 (s, 1H), 2.03-1.85 (m, 2H), 0.78-0.60 (m, 2H), −0.7 (s, JSn-H=17.2 Hz, 6H); 13C NMR (C6D6) δ 122.2-107.5 (m), 28.5 (t), −3.0, −13.4; 19F NMR (CDCl3) δ −81.2 (3F), −117.1 (2F), −122.4 (2F), −123.4 (2F), −123.9 (2F), −126.6 (2F); 119Sn NMR (C6D6) δ −86.8; HRMS: calcd. 496.9597, found: 496.9563. IR (thin film): 1839 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.[H-].[Na+].C(OCC)(=O)C>C(OCCOCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1F
Agent: CCOCCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-fluoro-4-methoxybenzaldehyde (2.20 g, Ald) in 1,2-diethoxyethane (5 ml) was added with ethyl diethylphosphonoacetate (3.12 ml, TCI) and added with 60% sodium hydride (624 mg) under ice cooling. After being stirred for 10 minutes, the reaction mixture was warmed to room temperature, and stirred for 5 hours. The reaction mixture was added with ethyl acetate (90 ml), and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 7, 3.16 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25]CC)=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH3:44])[CH:39]=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([OH:25])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH3:44])[CH:39]=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:33])[F:34])[N:3]=1
Reactant: CCCc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:14][NH2:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Si]([O:23][CH2:24]C=O)(C(C)(C)C)(C)C.Cl>>[NH2:15][CH2:14][C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7][N:2]([CH2:1][CH2:24][OH:23])[CH2:3][CH2:4]1
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Product: NCC1(c2ccccc2)CCN(CCO)CC1

Procedure:
The title material was prepared as described for the synthesis of (1-methyl-4-phenylpiperidin-4-yl)methanamine (Example B above) in using 2-(tert-butyldimethylsilyloxy)acetaldehyde and by doing an acidic work-up (HCl 5N) after the reductive amination to remove the protecting group. LC/MS (M+H)+: 235. HPLC ret. time (Condition A): 0.143 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:27]([O:29][CH2:30][CH3:31])=[CH2:28].C(=O)([O-])O.[Na+]>O.O1CCCC1>[CH2:27]([O:29][CH:30]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:31])[CH3:28]
Reactant: C=COCC
Reactant: COc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)Oc1cccc(OC)c1

Procedure:
2600 mL of tetrahydrofuran and 650.4 g (5.24 mol) of 3-methoxyphenol were added to a 15 L four-necked round bottom flask under a nitrogen atmosphere. Subsequently 65.8 g (0.26 mol) of pyridinium p-toluenesulfonate was added to this tetrahydrofuran solution and stirring was started. This mixture was cooled in a temperature-controlled bath set to 8° C. and 760.1 g (10.54 mol) of ethyl vinyl ether was added dropwise to the reaction mixture for about 1.5 hours. The reaction mixture was stirred at the same temperature for 2.7 hours and then the temperature of the temperature-controlled bath was set to 15° C. It was further stirred for about 2 hours from a time point when the inner temperature exceeded 14° C. The temperature of the temperature-controlled bath was set to 8° C., and at a time point when the inner temperature reached almost 10° C., 715.2 g of 8% sodium hydrogen carbonate aqueous solution [prepared by dissolving 57.2 g of sodium hydrogen carbonate in 658 mL of water] was added dropwise to the reaction mixture over 10 minutes. The reaction mixture was transferred to a 20 L separatory funnel and added with 1040 mL of water and added and extracted with 4550 mL of toluene and the organic layer was washed with 1300 mL and 650 mL of water twice. The obtained organic layer was concentrated in vacuo at a bath temperature of 40° C. and a pale yellow oil containing the title compound was obtained.