Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>>[N:21]1([CH2:20][CH2:19][N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:41]6[CH:40]=[N:39][N:38]([CH2:37][CH2:36][OH:35])[CH:42]=6)[CH:28]=[CH:27][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3CCN3CCOCC3)nc1-2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCN4CCOCC4)nc2-3)cn1

Procedure:
Following the procedure for 258, 8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 467. MS (ESI+) 494.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.38 (dd, J=8.3, 1.7, 1H), 7.30 (d, J=1.7, 1H), 4.95 (t, J=6.5, 2H), 4.91 (t, J=5.3, 1H), 4.39 (t, J=5.0, 2H), 4.16 (t, J=5.7, 2H), 3.77 (q, J=5.6, 2H), 3.51-3.38 (m, 6H), 2.82 (t, J=6.5, 2H), 2.46-2.36 (m, 4H)
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:32][C:33](Cl)=[O:34])[CH2:29][CH2:30][CH3:31]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:33]([O:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])[C:6]1=[O:14])[CH3:18]
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Reactant: CCCCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)N1C(=O)[C@H](O[Si](CC)(CC)CC)[C@@H]1c1ccco1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
(3R,4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.58 g, 2.17 mmol) in 30 mL of dichloromethane was stirred with diisopropylethyl amine (0.4 mL, 2.30 mmol) and butylchloroformate (0.3 mL, 2.36 mmol) in addition to a catalytic amount of DMAP. The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 3:1 hexane/ethyl acetate) to give 523 mg of product (Y: 65%); IR(KBr) 1820, 1734, 1318, 1018, 734 cm-1 ; 1H-NMR (CDCl3, 300 MHz) δ 7.38 (m, 1H), 6.35 (m, 2H), 5.09 (ABq, J=15.5, 5.6 Hz, 2H), 4.14 (m, 2H), 1.56 (m, 2H), 1.28 (s, 2H), 0.87 (t, J=8.7 Hz, 3H), 0.82 (t, J=7.9, 9H), 0.50 (m, 6H); 13C-NMR (CDCl3, 75.5 Hz) δ 165.4, 149.1, 147.6, 142.9, 110.5, 109.9, 77.7, 66.6, 55.9, 30.5, 18.8, 13.6, 6.3, 4.3; DCIMS M+H calcd for C18H29NO5Si: 368, Found: 368.
Reaction SMILES: NN.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4]>CCO.[Pd]>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC(C)N1CCC(c2ccc(N)cc2)CC1
Yield: 72.2 %

Procedure:
Hydrazine (35% by weight in water, 0.67 mL, 7.2 mmol) and 10% Pd/C (38 mg, 0.03 mmol) are added to a solution of 1-isopropyl-4-(4-nitrophenyl)piperidine (180 mg, 0.72 mmol) in EtOH (10 mL) and the mixture is heated at reflux for 3 h. After cooling, the mixture is filtered through celite and the solvent evaporated. The residue is redissolved in DCM (25 mL), dried over MgSO4 and the solvent evaporated to afford the desired compound as a pale yellow solid (113 mg, 0.52 mmol) which was used without further purification.
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH2:36][CH2:37][CH2:38][CH2:39]O)[CH3:35])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[CH2:50]([N:52](CC)CC)C.CS(Cl)(=O)=O.CN.CO>ClCCl>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH3:35])[CH2:36][CH2:37][CH2:38][CH2:39][NH:52][CH3:50])=[CH:29][CH:28]=2)[CH2:14][CH2:15]1
Reactant: CCN(CC)CC
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N(C)CCCCO)cc1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: CNCCCCN(C)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
The compound (107 mg, 0.159 mmol) obtained in Example 80a was dissolved in dichloromethane (6 mL), triethylamine (0.044 mL, 0.32 mmol) and methanesulfonyl chloride (0.018 mL, 0.24 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Triethylamine (0.044 mL, 0.32 mmol) and methanesulfonyl chloride (0.018 mL, 0.24 mmol) were further added under ice cooling, then a 40% methyl amine-methanol solution (6 mL) was added, and the mixture was stirred at room temperature for 14 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate:methanol=1:1:0→0:1:0→0:9:1, v/v/v) to give the title compound (84 mg; yield, 77%) as a colorless oily substance.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:20](=[O:23])[CH2:21][CH3:22])[C:4]=1[C:2]#[N:3]
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCC(=O)Cl
Agent: [Cl-]
Product: CCC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 191a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 191b) and propionyl chloride in 90% yield as a clear syrup. MS 274 (MH+).
Reaction SMILES: [CH3:1][C@:2]12[C:11]([CH3:13])([CH3:12])[C@H:8]([CH2:9][CH2:10]1)[C:4]1([CH2:7][CH2:6][CH2:5]1)[C:3]2=O.[CH:15]([NH2:17])=[O:16]>C(O)=O>[CH3:1][C:2]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:4]1([CH2:7][CH2:6][CH2:5]1)[CH:3]2[NH:17][CH:15]=[O:16]
Reactant: NC=O
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C21CCC1
Solvent: O=CO
Product: CC1(C)C2CCC1(C)C(NC=O)C21CCC1
Temperature: 175 °C
Reaction time: 72 h
Yield: 84.2 %

Procedure:
A mixture of (1S,4R)-4,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-one (1.60 g, 8.32 mmol) and formamide (10 mL) in formic acid (7 mL) was stirred at 175° C. for 72 h. The reaction mixture was cooled to ambient temperature, poured into 200 mL of ice-water, and extracted with ether (2×50 mL). The combined ether extracts were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated to obtain N-(4,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-yl)formamide (1.55 g, 84.2% yield) as gum.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][N+:13]=3[O-])=[C:9]([OH:11])[NH:10][C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:14][N:13]=3)=[C:9]([OH:11])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(Br)nc12
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1[nH]c2ccc(Br)nc2c1-c1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
728 mg of 2-(5-Bromo-2-hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-(morpholinomethyl)pyridine 1-oxide from example 4.1 were dissolved in ethyl acetate (20 mL) and 627 μL phosphorus trichloride (7.19 mmol) was added. After stirring the resulting suspension at ambient temperature for 2 days the precipitate was removed by filtration, washed with ethyl acetate, and dissolved in water. The aqueous layer was basified by addition of solid NaHCO3 and extracted with ethyl acetate (6×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was further purified by flash chromatography yielding the titled compound as a yellow foam (335 mg, 48%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][N:36]3[CH2:37][CH2:38][N:33]([C:30](=[O:32])[CH3:31])[CH2:34][CH2:35]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Nc1ncnn2c(CCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 65.2 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-bromo-ethyl)-pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (70 mg, 0.156 mmol), 1-acetyl-piperazine (40.1 mg, 0.313 mmol, 2.0 eq), triethylamine (20.6 mg, 0.20 mmol, 1.3 eq), and sodium iodide (2.3 mg, 0.016 mmol, 0.1 eq) in anhydrous DMF (1.6 mL) was stirred at 50° C. for 15 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aqueous brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then elided with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-hexane to provide the title compound (50.3 mg, 65%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.89 (s, 1H), 7.80 (dd, 1H), 7.57 (s, 1H), 7.36 to 7.30 (m, 5H), 7.13 (dd, 1H), 6.65 (s, 1H), 5.65 (s, 2H), 3.40 (q, 4H), 3.07 (t, 2H), 2.68 (t, 2H), 2.45 (t, 2H), 2.38 (t, 2H), 1.97 (s, 3H); ES-MS m/z 495.3 [M+H]+, RT (min) 2.02.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[CH:9]=1.C(O)(=O)C.[Br:56]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:49][Si:46]([CH3:47])([CH3:48])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:9]=1[Br:56]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(C(C)(C)O)nc4)c3n1)C2
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(C(C)(C)O)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Yield: 99.5 %

Procedure:
tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (0.500 g, 0.676 mmol) was dissolved in acetic acid (3.5 mL, 62 mmol) and N-bromosuccinimide (144.2 mg, 0.8105 mmol) was added in a single portion, and the reaction was monitored by HPLC. The reaction was complete in less than 10 min and the mixture was diluted with ethyl acetate and poured into a 1:1 mixture of saturated aq. sodium bicarbonate and aq. sodium thiosulfate (20%). The layers were separated and the organics washed several times with sodium bicarbonate solution then brine. The organics were dried with magnesium sulfate, filtered and concentrated to provide 550 mg of the desired material.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[N:31]1([S:35](C2C=C(C=C(C(F)(F)F)C=2)C(O)=O)(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>>[N:31]1([S:35]([C:2]2[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[C:5]([N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[CH3:8])=[O:6])(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCC2)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-(azetidine-1-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 16.5 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). Colorless foam (43%). MS (ESI): m/z=524.13 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35]([C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:43]3[CH:44]=[C:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[CH:40]=[CH:41][C:42]=3[O:48][CH3:49])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 80 °C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 25 mg; 0.041 mmol), (5-tert-butyl-2-methoxyphenyl)boronic acid (11.1 mg; 0.053 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (2.7 mg; 0.0041 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) were combined in a sealed tube and heated at 80° C. for 1.5 h. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-30% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-tert-butyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=648.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.83 (m, 2H), 7.78 (s, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.44-7.36 (m, 2H), 7.18 (dd, J=6.7, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.20 (d, J=16 Hz, 1H), 5.16 (d, J=11.2 Hz, 1H), 4.38 (d, J=15.8 Hz, 1H), 3.80 (s, 3H), 3.41-3.34 (m, 1H), 2.29-2.24 (m, 1H), 1.88-1.81 (m, 1H), 1.32 (s, 9H), 1.02 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:12])[CH:6]([CH3:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCN1c2nc(Cl)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
To a stirred solution of 2-chloro-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (2.0 g, 7.4 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 ml, 74 mmol), cupric acetate (2.70 g, 14.8 mmol) and phenylboronic acid (1.81 g, 14.8 mmol) followed by 4 Å molecular sieves (3.0 g). The reaction mixture was stirred for 48 h at room temperature with an air balloon. The mixture was then filtered over celite. The filtrate was washed with aqueous saturated sodium bicarbonate (2×50 ml), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel using 2% methanol in dichloromethane as eluent to give the titled product. (yield: 39%). 1HNMR (300 MHz, CDCl3): δ 0.91-1.01 (m, 6H), 1.49-1.75 (m, 6H), 3.12-3.20 (m, 1H), 4.18-4.21 (m, 1H), 4.30-4.45 (m, 1H), 7.10 (s, 1H), 7.20-7.39 (m, 2H), 7.42-7.65 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[Br:1][C:2]1[C:3]([O:10][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCOCCl
Reactant: O=Cc1cccc(Br)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(Br)cccc1C=O
Reaction time: 1 h
Yield: 78.4 %

Procedure:
3-Bromo-2-hydroxybenzaldehyde (1.5 g, 7.5 mmol) was dissolved in dichloromethane (25 mL) and diisopropylethylamine (2 mL, 11.3 mmol) was added to the solution. The mixture was stirred while 2-methoxyethoxymethyl chloride (0.94 mL, 8.3 mmol) was added dropwise. The mixture was stirred for 1 hour and then washed with 5% citric acid solution (5 mL) until the washings were acidic, dried and concentrated by evaporation. Product was purified from the residue by chromatography (silica gel, 30% ethyl acetate/hexanes) to give 3-bromo-2-(2-methoxy-ethoxymethoxy)benzaldehyde (1.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(C)(C)C.[Na+].C(OCC)(=O)C>C(COC)OC>[CH2:14]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccccc1C1CC1C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(CNc2ccccc2C2CC2C2CC2)cc1
Reaction time: 24 h
Yield: 87.1 %

Procedure:
3 g of 2-(2-chlorophenyl)bicyclopropyl (15.6 mmol, trans/cis ratio of about 2:1), 2.5 g of benzylamine (23.4 mmol), 2.4 g of sodium tert-butanolate (25 mmol), 35 mg of Pd(II) acetate (0.16 mmol) and 60 mg of R(−)-di-tert-butyl-[1-[(S)-2-(dicyclohexylphosphanyl)-ferrocenyl]ethyl]phosphine (0.11 mmol) are dissolved in 30 ml of dimethoxyethane. The reaction mixture is heated to the reflux temperature of the solvent and is stirred for 24 hours. After cooling, ethyl acetate is added and the organic phase is washed with water. The solvent is removed using a water jet vacuum and the residue is dried. The product is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 1:15). 3.58 g of benzyl(2-bicyclopropyl-2-yl-phenyl)amine (87% of theory) are obtained in the form of a brown oil (trans/cis ratio of about 2:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2N=C(C3C=CC([N+]([O-])=O)=CC=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[NH4+:22].[OH-]>>[NH2:10][C:7]1[CH:6]=[C:5]([NH2:22])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cc(N)c([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 4-amino-2-chloro-5-nitropyridine (4) (1.0 g, 5.76 mmol) in 50 ml 28% NH4OH was heated in a sealed tube at 120° C. for overnight. After cooling the reaction mixture to room temperature afforded orange red solid 5 (0.770 g, 77%). 1H NMR (DMSO-d6, 500 MHz): δ 8.66 (1H, s), 7.35 (1H, br s), 6.73 (1H, brs), 5.67 (1H, s); EIMS m/z: 155.2 (M+1), 153.2 (M−1)
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][S:7]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:9])=[O:8])C.O.[OH-].[K+].Cl>C1COCC1>[CH2:14]([CH:5]([CH2:6][S:7]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:9])=[O:8])[C:4]([OH:21])=[O:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of 2-benzyl-3-tert.-butylsulphonyl-propionic acid ethyl ester are dissolved in 8 ml of THF and then reacted with 5 ml of water and 0.88 ml of 2N potassium hydroxide solution. The mixture is stirred overnight at room temperature, neutralised with 0.88 ml of 2N hydrochloric acid and concentrated by evaporation. The residue is purified by flash chromatography on 30 g of silica gel 60 (eluant H). Yellow oil; m/e 284; 1H-NMR (DMSO-d6): 1.27 ppm (s, 9H); 2.73-3.1 (m, 4H); 3.2-3.5 (m, 1H); 7.2-7.4 (m, 5H); 12.5 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1)#[N:10]
Reactant: N#CCc1ccccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred mixture containing 5.88 g (0.03 mol) of (2-bromo-phenyl)-acetonitrile, 4.978 g. (0.03 mol) of 4-carboxyphenylboronic acid, 8.29 g (0.06 mol) of potassium carbonate and 0.52 g of dichlorobis(triphenylphosphine)palladium(II) in 46 mL of water and 25 mL of 1,4-dioxane was heated under reflux for two hours in an atmosphere of nitrogen. The reaction mixture was allowed to cool to room temperature and filtered. The dioxane was removed in vacuo and the residue diluted with 100 mL of water and then acidified with 20% hydrochloric acid. The crude product (1.2g) was recrystallized from ethanol to give a solid, m.p. 218-220° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]C)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CO.[OH-].[Na+].Cl>O>[NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(N)c(C(=O)O)nc1Cl
Temperature: 25 °C

Procedure:
A mixture of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate (100 g; 494 mmol), methanol (1 l) and NaOH (6 mol/l in water; 240 ml; 1.44 mol) is refluxed for 3 h. The mixture is allowed to cool to r.t. and then neutralized by addition of hydrochloric acid (6 mol/l in water; approx. 240 mL). Water (200 ml) is added. The precipitate formed is filtered off with suction, washed with water and dried at 60° C.