Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][CH:28]1[C:33]([N:43]2[C:55](=[O:56])[C:54]3[S:53][C:52]4[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=4[C:46]=3[CH2:45][CH2:44]2)(B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:57])[CH:30]=[CH:29]1)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:26][CH2:27][C:28]1[C:33]([N:43]2[C:55](=[O:56])[C:54]3[S:53][C:52]4[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=4[C:46]=3[CH2:45][CH2:44]2)=[CH:32][C:31]([F:57])=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCC1C=CC(F)=CC1(B1OC(C)(C)C(C)(C)O1)N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OC4CN(C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 40.5 %

Procedure:
A mixture of 199f (434 mg, 1.2 mmol), (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b (600 mg, 1.2 mmol), PdCl2(dppf) (134 mg, 0.18 mmol), K3PO4 (150 mg), and NaOAc (100 mg) in MeCN (8 mL) and water (2 mL) was heated at 110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuo. The residue was purified on reverse phase Combi-flash to give 199g (320 mg, 41%). MS: [M+H]+ 658.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:56](OC)[CH3:57])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].CO[C@H:62]([CH3:72])[C@H:63](NC(OC)=O)[C:64](O)=O>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:56]1[CH:57]=[CH:64][CH:63]=[CH:62][CH:72]=1)[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:44])[CH3:45])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 823 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].Cl.Cl.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:30][CH2:29][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C@H:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[C:17]=3[CH2:16]2)=[CH:11][C:10]=1[C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:30][CH2:29][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C@H:24]4[CH2:28][CH2:27][N:26]([C:1]([Cl:4])=[O:2])[CH2:25]4)[C:17]=3[CH2:16]2)=[CH:11][C:10]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)Cl)C4)c3C2)cc1C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To CH2Cl2 (5 mL) in a round bottomed flask was added phosgene (20% solution in toluene, 0.20 mL, 0.379 mmol) and the resulting solution cooled to 5° C. under argon. A solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (50.0 mg, 0.126 mmol) and triethylamine (0.053 mL, 0.380 mmol) in CH2Cl2 (1.0 mL) was added and the mixture allowed to warm to room temperature with stirring under argon over 1 h. Evaporated to dryness by bubbling a stream of argon into the mixture to give a brown gum. Dissolved in CH2Cl2 (3 mL) to give (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl chloride as a solution in CH2Cl2. LCMS: 458.4 [M+1]+, Rt(7)=1.38 min. This solution was used without further purification. 1.5 mL of this solution was added to a solution of piperidin-4-ol (6.4 mg, 0.063 mmol) and triethylamine (0.053 mL, 0.380 mmol) in CH2Cl2 and the mixture stirred at room temperature under argon for 1 h. N,N-dimethylformamide (0.5 mL) was added and stirring continued for 2 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (2 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give (4-hydroxy-piperidin-1-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone as a pale yellow powder (22 mg, 64% yield). 1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 1.35-1.57 (m, 2H) 1.80-1.94 (m, 2H) 2.20-2.31 (m, 2H) 2.94-3.09 (m, 4H) 3.45-3.87 (m, 10H) 3.98 (s, 3H) 4.17 (s, 2H) 5.70-5.76 (m, 1H) 7.78 (d, 1H) 8.13 (d, 1H) 8.58 (s, 1H) LCMS: [M+H]+=523.2, Rt(1)=1.58 min.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][CH:46]=O)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)#[N:31].C(C1C=CC([C@H]2CC[C@H](CCCC=O)CC2)=CC=1)#N>O1CCCC1.O.C1(C)C=CC=CC=1>[CH3:2][O:3][CH:4]=[CH:46][CH2:45][CH2:44][C@H:41]1[CH2:40][CH2:39][C@H:38]([C:35]2[CH:34]=[CH:33][C:32]([C:30]#[N:31])=[CH:37][CH:36]=2)[CH2:43][CH2:42]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
Commercially available methoxymethyltriphenylphosphonium chloride (257 g, 0.75 mol) was added to tetrahydrofuran (500 ml), followed by adding potassium t-butoxide (84.2 g, 0.75 mol) in argon atmosphere with stirring at -10° C. over 40 minutes, agitating the reaction solution at 0° C. for one hour, dropwise adding a solution of 3-[trans-4-(4-cyanophenyl)cyclohexyl]-1-propanal (121 g, 0.50 mol) obtained according to the method of Example 3 (i), in tetrahydrofuran (400 ml) at -10° C. over one hour, agitating the reaction mixture at 0° C. for one hour, further agitating at 20° C. for 2 hours, adding toluene (1 l) and water (1 l) to the reaction mixture at 0° C., four times washing the resulting toluene solution with water (1 l), drying over anhydrous magnesium sulfate, separating the drying agent, distilling off toluene, purifying the resulting residue according to silica gel column chromatography using heptane as an eluent to obtain trans-1-(4-methoxy-3-butenyl)-4-(4-cyanophenyl)cyclohexane (110.8 g, 0.41 mol), adding to the total quantity of this compound, tetrahydrofuran (1.5 l) and 2N-hydrochloric acid (0.4 l), heating the mixture under reflux, with stirring for one hour, cooling the resulting reaction mixture, adding diethyl ether (0.5 l) and water (1 l), three times washing the resulting diethyl ether solution with water (0.5 l), drying over anhydrous magnesium sulfate, separating the drying agent, concentrating under reduced pressure to obtain a residue (120 g), and recrystallizing from a mixed solvent of heptane and ethyl acetate (3:1) to obtain 4-[trans-4-(4-cyanophenyl)cyclohexyl]-1-butanal (93.0 g, 0.36 mol).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
70 g of 1-acetylisonipecotoyl chloride are slowly added to a stirring mixture of 93.0 g of aluminum chloride in 150 ml of fluorobenzene. After total addition, the mixture is refluxed for one hour. The mixture is poured onto ice and the two resulting layers separate. The aqueous layer is extracted twice with chloroform and the extracts are added to the fluorobenzene which separated previously. The organic solution is dried and concentrated under reduced pressure leaving a crystalline white solid. The solid is recrystallized from a ligroindiisopropyl ether mixture, producing 1-acetyl-4-(4-fluorobenzoyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:26]=[C:27]([S:31]([NH:34][CH2:35][C:36]5([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][CH2:37]5)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl[CH2:44][C:45]([N:47]([CH2:51][CH2:52][CH3:53])[CH2:48][CH2:49][CH3:50])=[O:46].C(=O)(O)[O-].[Na+].[Na+].[I-]>CN(C=O)C>[CH2:48]([N:47]([CH2:51][CH2:52][CH3:53])[C:45]([CH2:44][O:41][C:40]([C:36]1([CH2:35][NH:34][S:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:23]([N:20]3[CH2:21][CH2:22][C:15]4([NH:14]/[C:13](=[N:12]/[C:10]([C:3]5[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=5)=[O:11])/[NH:17][CH2:16]4)[CH2:18][CH2:19]3)=[O:24])[CH:26]=2)(=[O:32])=[O:33])[CH2:37][CH2:38][CH2:39]1)=[O:42])=[O:46])[CH2:49][CH3:50]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCC5(C(=O)O)CCC5)c4)CC3)N2)nc1Cl
Reactant: CCCN(CCC)C(=O)CCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)COC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1-[(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-methyl]-cyclobutanecarboxylic acid (step 2) (350 mg, 0.564 mmol) in DMF (10 ml) was stirred at 50° C. with pre-activated molecular sieves for 30 min. 2-Chloro-N,N-dipropylacetamide (100 mg, 0.564 mmol), sodium bicarbonate (142 mg, 1.693 mmol) and NaI (8.46 mg, 0.056 mmol) were added and stirring continued at 50° C. After 3.5 h, the mixture was allowed to cool to RT and the molecular sieves were removed. The mixture was poured into water and the resulting white suspension was filtered, washed with water and dried in vacuo. The solid was dissolved in DCM and diethyl ether was added to yield a white precipitate which was collected by filtration and dried under vacuum overnight to afford the title product; 1H NMR (400 MHz, DMSO-d6) δ 9.30-7.74 (4H, br hump), 7.88 (1H, d), 7.79 (1H, br s), 7.69 (1H, dd), 7.66 (1H, m), 7.11-6.67 (1H, br hump), 6.84-6.61 (2H, br s), 4.76 (2H, s), 3.82-3.29 (4H, m), 3.44 (2H, s), 3.18-3.14 (4H, m), 3.15 (2H, br s), 2.31-1.95 (4H, m), 1.81 (2H, m), 1.83-1.65 (4H, m), 1.54-1.45 (4H, m), 0.86 (3H, t), 0.80 (3H, t); LC-MS Rt 3.62 mins; 761.7 [M+H]+, Method 10minLC_v003.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:29])[C:17]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:29])[C:17]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:31][C:32]#[N:33]
Reactant: N#CCBr
Reactant: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A mixture of N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (4.6 g, 10.2 mmol), prepared in the previous step, bromoacetonitrile (856 μL, 12.3 mmol) and potassium carbonate (7.0 g, 50 mmol) in 75 mL of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-N,1-dimethyl-1H-indole-3-carboxamide (3.4 g, 68%) as an off-white solid, mp 202-206° C. Elemental Analysis for C26H22BrN3O2. Calc'd: C, 63.94; H, 4.54; N, 8.60. Found: C, 50.59; H, 3.30; N, 8.00
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=[CH2:4].N1C=CC=CC=1.P(Br)(Br)[Br:22]>CCCCCC>[Br:22][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: C=CC(C)(O)CCC=C(C)CC(C)C
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=CCBr)CCC=C(C)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
19.8 g. of 3,7,9-trimethyl-1,6-decadien-3-ol, 100 ml. of hexane and 1 ml. of pyridine and cooled to -15° C. and treated dropwise over a period of 1.5 hours with a solution of 4 ml. of phosphorus tribromide in 50 ml. of hexane while maintaining the temperature between -15° and -10° C. The mixture is stirred for a further 90 minutes while slowly warming to room temperature. For the working-up, the mixture is poured on to 50 ml. of ice-water, the organic phase is separated and washed once with 20 ml. of 10% soda solution, once with 50 ml. of semi-saturated aqueous sodium chloride solution and once with 50 ml. saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 1-bromo-3,7,9-trimethyl-2,6-decadiene.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:17]N(C=O)C.[H-].[Na+].IC>O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CN(C)C=O
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
7 g (24.7 mmol) of 3-bromo-2-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 40 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. 890 mg (29.6 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 1.7 ml (27 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 7.3 g (99%) of the expected product are collected in the form of an oil which crystallizes slowly. Melting point 77-8° C.
Reaction SMILES: C[O-].[Na+].[C:4]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][SH:34])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[F:5].[CH2:35]1[O:37][CH2:36]1.Cl>O.CO>[C:4]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][S:34][CH2:35][CH2:36][OH:37])([F:30])[F:31])([F:27])[F:28])([F:24])[F:25])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[F:5]
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: C1CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A 500 ml flask is charged with 100 ml of methanol, 5.4 g (0.1 mole) of sodium methoxide, and 53 g (0.1 mole) of (CF3)2CF(CF2)6C2H4SH and the mixture stirred for 30 minutes at 5° C. To this is added 4.6 g (0.105 mole) of liquid ethylene oxide keeping the temperature below 5°. After stirring for 1 hour, 100 ml of water is added and the product acidified to litmus with conc. hydrochloric acid. Extraction with 1,1,2-trichloro-1,2,2-trifluoroethane and solvent evaporation affords 41 g of (CF3)2CF(CF2)6C2H4SC2H4OH, m.p., 69°-71°.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:9][C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)[C:11]([CH3:12])=[CH:10][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C)c(Br)cc2o1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cc(C)c(-c3ccc(N)nc3)cc2o1
Temperature: 85 °C
Yield: 81 %

Procedure:
A mixture of 6-bromo-2,5-dimethybenzoxazole (48) (148 mg, 0.65 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (171 mg, 1.2 eq), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (A-Phos) (55 mg) and K3PO4 (137 mg, 0.6 mmol) in 1.5 ml ACN, 1.5 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting red solid was dissolved in DCM and subjected to silica gel column purification using 0-100% B (A: hexane; B: EA) to furnish 126 mg 5-(2,5-dimethylbenzoxazol-6-yl)-2-pyridylamine (49) as yellow solid (yield: 81%, purity>95%)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:9])[N:6]([CH3:8])[N:7]=1)[CH3:2].[CH:10]1(C(=O)CC#N)CC[CH2:11]1>>[CH:1]1([C:3]2[CH:4]=[C:5]([NH2:9])[N:6]([CH3:8])[N:7]=2)[CH2:11][CH2:10][CH2:2]1
Reactant: CCc1cc(N)n(C)n1
Reactant: N#CCC(=O)C1CCC1
Product: Cn1nc(C2CCC2)cc1N

Procedure:
This is synthesized in an analogous manner to 5-ethyl-2-methyl-2H-pyrazol-3-ylamine except using 3-cyclobutyl-3-oxopropionitrile instead of 3-oxo-pentanenitrile.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH:14]([C:23]1[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1)[N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH:14]([N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1)[C:23]1[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1)=[O:6]
Reactant: Cn1cc(C(CN)N2CCC(F)(F)CC2)ccc1=O
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cn1cc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)ccc1=O

Procedure:
From 2,3-dichlorobenzoic acid and 5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-1-methylpyridin-2(1H)-one.
Reaction SMILES: [CH2:1]([N:9]1[CH2:16][CH:15]2[C:17](=O)[CH:11]([CH2:12][Se:13][CH2:14]2)[CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].C1(C)C(C)=CC=CC=1>C(O)COCCOCCO>[CH2:1]([N:9]1[CH2:16][CH:15]2[CH2:17][CH:11]([CH2:12][Se:13][CH2:14]2)[CH2:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1C2C[Se]CC1CN(CCc1ccccc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: OCCOCCOCCO
Product: c1ccc(CCN2CC3C[Se]CC(C3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A jacketed flask was charged with a mixture of 7-phenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (1.3 g, 4.2 mmol) N2H4 (95%, 2.0 g, 59 mmol), and KOH (85%, 6.0 g, 91 mmol) in triethylene glycol (40 mL). The flask was equipped for simple distillation under a rapid stream of nitrogen. The reaction mixture was heated to 140°-145° C. by boiling xylene contained in the jacket. Heating was continued under a nitrogen stream for 5 hours. During this time, a small amount of water and hydrazine distilled out. The resulting clear, light brown solution was cooled in a water bath to room temperature and was then poured into ice-water (200 mL). The white suspension which formed was extracted with ether (5×40 mL). The combined ether extracts were washed with brine (30 mL) and dried (K2CO3) overnight. After filtering out the desiccant, this ether solution was cooled to 0°-5° C. in an ice bath and 60% HClO4 (1.0 g, 6.0 mmol) was added dropwise, very slowly. After stirring overnight, the resulting orange precipitate was filtered and recrystallized (methanol, decolorizing carbon) to give 0.67 g (40%) of 7-phenethyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate as white plates: mp 249°-250° C. (dec): IR (KBr) cm-1 3400, 1140; 1H NMR (DMSO-d6) δ1.73 [br d, 1H, H(9), J=14.0 Hz], 1.89 [br d, 1H, H(9), J=13.8 Hz], 2.41 [br s, 2H, H(1,5)], 2.64 [d, 2H, H(2,4)ax, J=12.1 Hz], 3.07 [t, 2H, H(11-ArCH2), J=7.9 Hz], 3.20 [d, 2H, H(2,4)eq, J=12.2 Hz], 3.33 [m, 4H, H(10-NCH2), (6,8)ax ], 3.86 [d, 2H, H(6,8)eq, J=12.3 Hz], 7.28-7.50 [m, 5H, Ar--H], 8.89 [br s, 1H, H(7)]; 13C NMR (DMSO-d6) ppm 21.9 [t, C(2,4)], 25.3 [d, C(1,5)], 28.5 [t, C(9) or C(11-ArCH2)], 29.9 [t, C(11-ArCH2) or C(9)], 56.7 [y, C(6,8)], 58.8 [t, C(10-NCH2)], 126.8 [d, C(4')], 128.5 [d, C(2',6',3',5')], 136.2 [s, C(1'))]; 15N NMR (DMSO-d6) ppm 48.25 [N(7)]; 77Se NMR (DMSO-d6) ppm 88.42 [Se(3)]. Analysis calculated for C15H22ClNO4Se: C, 45.64; H, 5.62; N, 3.55; Se, 20.00. Found C, 45.77; H, 5.80; N, 3.48; Se, 19.85. ##STR26##
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15]1C=C[CH:17]=[C:16]1CC(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:16](=[S:15])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h

Procedure:
A solution of 2.2 g of N—BOC-3-(R)-hydroxy-piperidine in 10 ml of THF is added under argon and 1 ml of thiolacetic acid to a solution of 3.4 g of triphenylphosphine and 2.65 ml of azadicarbonic acid-isopropylate in 10 ml of THF. The mixture obtained is kept for 18 hours at 70°, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. N—BOC-3-(S)-thioacetoxy-piperidine is obtained. 1H-NMR (CDCl3): 3.78 (dd,1H,NCH2CHS, J=3.1 Hz, J=13.3 Hz), 3.5-3.6 (m,2H, CHSC═O, NCH2CH2), 2.32(s,3H,SC═OCH3),1.46(s,9H, tert.butyl)