Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(F)c(F)c1C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(N)ccc(F)c1F
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 2-amino-5,6-difluoro benzoic acid (3.78 g, 21.8 mmol) in tetrahydrofuran (500 mL) was added EDCl.HCl (8.5 g, 44.0 mmol, 2.0 equiv.), HOBT (5.9 g, 44 mmol, 2.0 equiv.) and ammonia as a 0.5M solution in dioxanes (218 mL, 109 mmol, 5 equiv.). The resultant slurry was stirred for 24 hours, and then solids removed by filtration through celite. The filtrate was taken to a residue under reduced pressure and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (Ethyl acetate/Hexanes) to afford analytically pure 2-amino-5,6-difluorobenzamide as a white crystalline solid (2.73 g, 15.8 mmol, 72% Yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.78 (s, 2 H), 6.45 (ddd, J=9.16, 4.03, 1.83 Hz, 1 H), 7.10-7.18 (m, 1 H), 7.69 (d, J=11.00 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.Cl.[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[C:33]([F:39])[CH:32]=1>ClCCl.CN(C)C=O>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([S:12][CH3:13])=[CH:11][C:3]=2[O:2][CH3:1])=[C:33]([F:39])[CH:32]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: COc1cc(SC)ccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methoxy-4-(methylthio)benzoic acid (5.0 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. and treated with oxalyl chloride (6.6 mL, 75.6 mmol). A drop of N,N-dimethylformamide was added and the reaction was heated to a gentle reflux for 2 h. After cooling to room temperature, the solution was concentrated in vacuo to remove the excess oxalyl chloride, diluted with dichloromethane (53 mL) and cooled to 0° C. The resulting solution was treated with N,N-diisopropylethylamine (11.6 mL, 67 mmol) and 4-bromo-2-fluorobenzylamine hydrochloride (9.7 g, 40.2 mmol). The resulting solution was stirred at room temperature overnight, concentrated in vacuo, diluted with ethyl acetate and successively washed with 2 N HCl and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Rf 0.4 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 8.63 (t, J=6 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.50 (dd, J1=9.6 Hz, J2=2.1 Hz, 1H), 7.38 (dd, J1=8.4 Hz, J2=2.0 Hz , 1H), 7.28 (t, J=8.4 Hz, 1H), 6.94 (br s , 1H), 6.89 (dd, J1=5.7 Hz, J2=1.7 Hz, 1H), 4.46 (d, J=6 Hz, 2 H), 3.91 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>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.[Cu]I>[C:21]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)OC
Yield: 100 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.81 g, 2.58 mmol) with 1-decyne (0.95 mL, 5.16 mmol) using Pd(PPh3)2Cl2 and CuI gave 0.78 g (˜100%) of the title compound (191) as a dark brown oil. 1H NMR (400 MHz, CDCl3): δ 0.85-−0.90 (m, 3H), 1.20-1.40 (m, 8H), 1.40-1.55 (m, 2H), 1.60-1.70 (m, 2H), 2.47 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.8 Hz, J2=2.6 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H). LCMS (APCI): m/z 325 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:16]([CH2:17][C:5]2=1)[CH2:15][CH2:14][CH2:13]3.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[F:44][C:41]1[CH:42]=[CH:43][C:38](/[C:36](/[CH3:37])=[CH:35]/[N:7]2[C:8]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[C:5]3[CH2:17][N:16]4[CH:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:39][CH:40]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN1CCCC1C2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7-Methyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (45 mg, 0.198 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (3.76 mg, 0.0198 mmol), L-proline (2.1 mg, 0.0398 mmol) and K3PO4 (71 mg, 0.396 mmol) were added and the reaction mixture was stirred for min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (51 mg, 0.24 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by reverse phase HPLC. Yield: 22 mg as TFA salt; Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile Phase A: 0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10 min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1.0 mL/min, Retention time: 10.094 min, HPLC purity: 98.06%;
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](OCC)(OCC)[CH2:16][CH3:17])C.C(OC(=O)C)(=O)C>>[C:1]([C:9](=[C:15]([O:14][CH3:12])[CH2:16][CH3:17])[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#CCC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCC(OC)=C(C#N)C(=O)c1ccccc1

Procedure:
A solution containing 30 g. of benzoylacetonitrile, 36.4 g. of triethylorthopropionate and 57 g. of acetic anhydride is heated in an oil bath at 130° for 3 hours. The ethanol and excess acetic anhydride is distilled off and the residue is diluted with chloroform. The chloroform solution is passed quickly through Magnesol® and concentrated, then cooled to produce the title product. Similarly prepared is 2-benzoyl-3-methoxy-2-hexenonitrile and 2-benzoyl-3-methoxy-2-heptenonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][C:24]=1[CH3:30])[CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:17]([O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([O:16][C:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:25][C:24]=1[CH3:30])[CH3:18]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1C
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(Oc2cc(C)cc(OCc3ccccc3)c2)cc1C
Temperature: 130 °C
Reaction time: 20 h
Yield: 58.6 %

Procedure:
A mixture of 3-benzyloxy-5-methyl-phenol (3.24 g, 15.1 mmol), 3-(4-fluoro-2-methyl-phenyl)-acrylic acid ethyl ester (3.15 g, 15.1 mmol) and 325 mesh potassium carbonate (2.51 g, 18.2 mmol) in dry DMSO (40 mL) is heated to 130° C. and stirred for 20 hours under N2. The reaction is cooled and acidified with 1 N HCl (30 mL). The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.56 g (58%) of the title compound. Rf=0.39 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H26O4 402, found 403 (M+1, 100%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CO[C@H](C)C(=O)O
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (65 mg, 62%), MS (ISP) m/z=417.4 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (R)-2-methoxy-propanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].ClCC1OC(CCC2C=CC(C(F)(F)F)=CC=2)=NC=1C.FC(F)(F)C1C=CC(C(N)=O)=CC=1.ClC(C(C)=O)C([O-])=O.[Br:63]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:63])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(=O)C(Cl)C(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Yield: 68.1 %

Procedure:
To a refluxing mixture of 21.5 g 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester (synthesized according to the method described for 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole from 4-trifluoromethyl-benzamide and 2-chloroacetoacetate) in 180 ml tetrachloro-methane were added portionwise a mixture of 15.4 g N-bromosuccinimide and 4.73 g 2,2′-azobis(2-methylpropionitrile). The reaction mixture was heated under reflux for five hours. The cooled reaction mixture was filtered over a celite pad, the filtrate was evaporated in vacuo and the resulting residue was purified by chromatography on silica gel with the eluent petroleum benzene:dichloromethane=7:3 to provide 18.5 g 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester.
Reaction SMILES: N#N.[Si]([O:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][O:18][CH3:19])=[N:14][CH:13]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:19][O:18][CH2:17][C:15]1[S:16][C:12]([CH2:11][OH:10])=[CH:13][N:14]=1
Reactant: COCc1ncc(CO[Si](C)(C)C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1ncc(CO)s1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(methoxymethyl)thiazole (721 mg, 2.64 mmol) in THF (20 mL) was treated at 0° C. with TBAF (5.30 mL of a 1M solution in THF, 5.30 mmol) and the resulting mixture was stirred for 45 min at 0° C. The reaction mixture was diluted with EA, washed with sat. aq. NH4Cl and brine, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:9 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:9 hept-EA)=0.27. LC-MS-conditions 07: tR=0.41 min, [M+H]+=160.01.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][N:16]=[N+]=[N-])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH2:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1

Procedure:
trans-(4-Azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (24 g) in ethyl acetate (1 liter) is hydrogenated over platinumoxide (2.4 g) at ambient temperature under atmospheric pressure of hydrogen. The catalyst is filtered-off and the filtrate concentrated to yield trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester as an oil. Rf (C2) 0.41.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@H:13]([OH:17])[CH2:14][C:15]#[N:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([C@H:13]([OH:17])[CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CC[C@@H](O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC[C@@H](O)c1ccccc1

Procedure:
To a stirring suspension of lithium aluminum hydride in dry THF at 0° C. was added a solution of (R)-3-phenyl-3-hydroxypropanenitrile in dry THF under nitrogen. The ice bath was removed and then the reaction mixture was refluxed for 2 h. Excess lithium aluminum hydride was destroyed by adding H2O and EtOAc. The white precipitate obtained was filtered and washed with MeOH. The combined filtrate was concentrated to give (R)-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=3)[S:10][C:3]=12.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].C([O-])([O-])=O.[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.ClCCl>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CCOC(=O)Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 185 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A suspension of 373 (1.05 g, 3.26 mmol), 2-fluoro-4-nitrophenol (1.10 g, 7.00 mmol), and K2CO3 (2.0 g, 15 mmol) in diphenyl ether (10 mL) was heated with stirring to 185° C. for 3 h. The mixture was cooled, diluted with dichloromethane, filtered, and the filtrate was concentrated. Silica gel chromatography (75% ethyl acetate/hexanes) of the residue provided 374 (0.98 g, 68% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.52 (d, J=5.3, 1H); 8.46 (dd, J=10.4, 2.5, 1H); 8.20-8.17 (m, 1H); 7.89 (d, J=1.2, 1H), 7.77-7.74 (m, 1H); 7.75 (s, 1H); 7.69 (t, J=8.2, 1H); 6.86 (d, J=5.3, 1H); 5.04 (s, 2H); 4.17 (q, J=7.2, 2H); 1.22 (t, J=7.2, 3H). LRMS (M+H): 442.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH3:23])[CH:18]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:15]([F:14])[CH:16]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: Cc1ccc(C=O)cc1F
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 44.2 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column. 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18, found 305.9 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:26])[CH2:25][CH2:24]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4-bromomethyl-benzoic acid methyl ester (3.0 g; 15 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (3.77 g; 16.5 mmol) and potassium carbonate (4.35 g, 31.5 mmol) in 100 ml acetonitrile is stirred for 5 h at 80° C. Precipitates were removed by filtration and the solution is evaporated. The residue is purified by silica gel column chromatography (gradient: DCM/Methanol 98:2 to 95:5 to yield 4-(4-tert-Butoxycarbonylamino-piperidin-1-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]=1.C([Li])CCC.[I:24]I>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:24])=[CH:14][N:13]=1
Reactant: Fc1cccc(F)c1Nc1ccc(Br)cn1
Reactant: II
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Nc1ccc(I)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred solution of sodium hydride (2 eq.) in rigorously degassed THF (approximately 50 mL/g) at 0° C., was added dropwise a solution of (2,6-difluorophenyl)-(5-bromopyridin-2-yl)-amine (1 eq.) in THF (approximately 15 mL/g). The solution was allowed to warm slowly to room temperature over 1 hour, after which time the solution was cooled to −78° C. n-Butyllithium (approximately 1.6 M in hexanes, 1.1 eq.) was added dropwise over 15 minutes and the resultant solution was stirred at −78° C. for 1 hour. Zinc chloride/TMEDA complex (prepared as described by Isobe et al., Chem. Lett., 1977, 679) was added as a solid in a single portion and the solution was allowed to warm to 0° C. over 30 minutes, and was stirred at 0° C. for a further 1 hour. A solution of iodine (1.1 eq.) in THF (approximately 10 mL/g) was added and the solution was allowed to warm to room temperature. After stirring at room temperature for at least 1 hour, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The solution was extracted with diethyl ether (3 times approximately 50 mL/g of 5-Bromopyridin-2-yl)-(2,6-difluorophenyl)-amine used). The combined organic layer was washed successively with 10% aqueous sodium sulfite solution (approximately 50 mL/g), saturated aqueous sodium thiosulfate solution (approximately 50 mL/g) and water (approximately 50 mL/g), dried over MgSO4 and concentrated in vacuo to give the crude reaction product as an orange oil. Purification by column chromatography, using 10% ethyl acetate:hexane as eluant, provided (2,6-Difluoro-phenyl)-(5-iodo-pyridin-2-yl)-amine (Rf 0.22) in approximately 50% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12](O)=[O:13])=[CH:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>CCOCC.Cl.C1COCC1.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[O:13])=[CH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=[Mn]=O
Agent: Cl
Agent: [Al+3]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C=O)cc2c1
Yield: 32.7 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-methoxyindole-2-carboxylic acid (1.00 g) in Et2O (40 mL) was added LiAlH4 (280 mg) at 0° C., and the mixture was stirred under reflux for 3 hours. The mixture was treated with ethyl acetate, diluted with an aqueous hydrochloric acid solution, and extracted with ethyl acetate. The mixture was concentrated to give a crude alcohol compound (840 mg, 91%), which was dissolved in THF (10 mL), and stirred with MnO2 (4.20 g) at room temperature for 5 hours. The mixture was filtered on celite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 5-methoxyindole-2-carbaldehyde (300 mg, 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=O)=[CH:16][CH:15]=1)#[N:13].N>P(Cl)(Cl)(Cl)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1

Procedure:
3.1 g (0.02 mol) of 4-nitro-o-phenylenediamine and 3.7 g (0.023 mol) of 4-cyanophenylacetic acid are refluxed for 2 hours in 30 ml of phosphorus oxychloride. After cooling the mixture is neutralised with concentrated ammonia and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with methylene chloride/methanol (50:1). The desired fractions are concentrated by evaporation, the residue is triturated with ethyl acetate/ether, suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][NH:42][CH3:43]>>[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][N:42]([CH3:43])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CNCC(OC)OC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: COC(CN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1)OC

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (2,2-dimethoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 92-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.84-3.6 (m, 11H), 3.28 (m, 4H), 3.77 (m, 4H), 4.5 (s, 1H), 6.26-6.24 (m, 1H), 7.04 (d, J=12.0 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 7.47-7.65 (m, 5H), 7.82 (m, 1H), 7.99-8.01 (m, 1H), 8.29 (m, 1H), 10.45 (s, 1H).