Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](C)(C)(C)[CH3:2].Br[C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:9][S:10][C:11]=1[NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[CH3:18])=[O:14]>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.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>[F:27][C:21]1[CH:20]=[C:19]([C:8]2[C:7]([CH3:2])=[C:11]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[CH3:18])=[O:14])[S:10][N:9]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C[Sn](C)(C)C
Reactant: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Add PdCl2(PPh3)2 (0.15 g, 0.21 mmol) and Sn(CH3)4 (0.79 mL, 1.02 g, 5.71 mmol) to (R,R)—N-[4-bromo-3-(3-fluoro-4-methoxyphenyl)-isothiazol-5-yl]-2-methylcyclopropanecarboxamide (0.55 g, 1.43 mmol) in DMF (3 mL), and stir the reaction mixture at 130° C. in a sealed tube overnight. Dilute with EtOAc (100 mL) and brine (100 mL). Collect the organic phase, dry (K2CO3) and evaporate. Take up the resultant oil in 1:1 MTBE:KF (aqueous, 15%) (50 mL) and stir at reflux for 1 h. Pour the cooled solution over diatomaceous earth and filter with MTBE (100 mL). Collect the organic phase, dry (K2CO3) and evaporate. Chromatography over silica gel, eluting with 10-30% THF in hexane, affords (R,R)—N-[3-(3-fluoro-4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 49.2%. ES-MS: m/e 321.0 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(F)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(F)cc1CBr
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.C(Cl)(Cl)Cl>CN(C)C=O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7]
Reactant: BrCCCCBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CCCCN1CCCCBr
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
2-piperidone (1.98 g, 20.0 mmoles) was dissolved in 40 ml of dimethylformamide, 60% sodium hydride (840 mg, 21.0 mmoles) was added to the solution, and the mixture was stirred at 80° C. for 1 hour. After cooling the mixture to room temperature, 1,4-dibromobutane (21.6 g, 100 mmoles) was added, and the resulting mixture was stirred at room temperature for 12 hours. After chloroform was added to the reaction mixture, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with water, and the solvent was evaporated. The residue was purified by chromatography on a silica gel column to give 1.30 g (yield 28%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1CC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CC(=O)N1
Yield: 97.9 %

Procedure:
A solution of 4-(2-acetoxyvinyl)-2-azetidinone (10.0 g, 0.065 mole) in 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-(2-acetoxyethyl)-2-azetidinone (10.0 g) as a crystalline solid. Recrystallization from ether affords white crystals: M.P. 44°-7°; ir (CHCl3)μ 5.66, 5.74; nmr (CDCl3)τ3.44 (broad s, 1, NH), 5.82 (m, 2, CH2OCOCH3), 6.29 (m, 1, C--4H), 6.87 (1/2 AB pattern further split in four by C--4H and NH, 1, Jgem =12.8 Hz, J=4.5H JNH =1.9 Hz, 7.38 (1/2 AB pattern further split in four by C--4H and NH, 1, Jgem =12.8 Hz, J=2.3 Hz, JNH =1.0 Hz), 7.93 and 8.02 (s on m, total 5, OCOCH3 and CH2CH2OCOCH3, respectively).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:22]2[CH:21]([CH2:20][CH2:19][CH2:18][C:17]2=[O:23])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CCCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCC2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl-methoxymethyl-trimethylsilanylmethyl-amine (29.6 g, 0.12 mol) was added to a solution of cyclohex-2-enone (10 g, 0.104 mol) in 500 mL of dichloromethane at 0° C. followed by the dropwise addition of 10 mol % TFA dissolved in 2 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight and was quenched with 50 mL of saturated NaHCO3. The organic layer was washed with 500 mL of brine, dried with MgSO4 and solvent was evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 2-45% ethylacetate-hexane gradient to afford the subtitle compound. (13.8 g, 60%). MS calculated for C15H19NO +H: 230, observed: 230.
Reaction SMILES: [H-].[Na+].ClC(Cl)(O[C:7](=[O:13])OC(Cl)(Cl)Cl)Cl.[CH:15]1([NH:21][C:22]2[N:23]=[N:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:39][CH:40]([C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([CH:49]([CH3:51])[CH3:50])[C:43]=1[NH2:44])[CH3:41].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:51][CH:49]([C:45]1[CH:46]=[CH:47][CH:48]=[C:42]([CH:40]([CH3:41])[CH3:39])[C:43]=1[NH:44][C:7](=[O:13])[N:21]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:22]1[N:23]=[N:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:26]=1)[CH3:50]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCCCn1nnc(NC2CCCCC2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(N(C(=O)Nc2c(C(C)C)cccc2C(C)C)C2CCCCC2)n1
Reaction time: 168 h

Procedure:
A suspension of a 60% dispersion of sodium hydride in mineral oil (0.2648 g, 0.0066 mol) in a solution of triphosgene (0.4583 g, 0.001544 mol) and N-cyclohexyl-2-dodecyl-2H-tetrazol-5-amine (1.5540 g, 0.0046313 mol) in anhydrous tetrahydrofuran (15 mL) under a nitrogen atmosphere was refluxed for 4.5 days. To the mixture was added 2,6-bis(1-methylethyl)aniline (0.88 mL, 0.0047 mol) and diisopropylethylamine (0.89 mL, 0.0051 mol), and the reflux was continued for 7 days. The mixture was rotoevaporated, and the residue partitioned between diethyl ether and saturated sodium bicarbonate. The organic layer was washed with 1M hydrochloric acid and saturated sodium chloride, dried (MgSO4), and rotoevaporated to an oil. The oil was chromatographed on silica gel (430 g, 230-400 mesh) using PET ether-ethyl acetate (30:1, 14×400 mL) to give the title compound as an oil, yield 1.4522 g (58%) . 1H NMR (CDCl3): δ 8.8 (s, 1H), 7.3 (dd, 2H), 7.2 (d, 1H), 4.6 (m, 3H), 3.1 (septet, 2H), 2.1 (m, 4H), 1.8 (m, 4H), 1.6 (m, 2H), 1.3 (m, 32H), 0.9 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.CCOC(C)=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CC(C)c1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Temperature: 140 °C
Yield: 25.3 %

Procedure:
To a solution of 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 807 μmol) in NMP (3.2 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) and the mixture heated to 140° C. Over the next 36 h three additional portions of tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) were added at 12 h intervals. At 48 h the mixture was cooled, diluted with EtOAc, and washed with water and brine (2×). The organic layer was concentrated onto silica and purified by chromatography (70% to 100% EtOAc in hexanes) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 25%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.49 (s, 1H), 8.22 (s, 1H), 8.06 (br. s, 1H), 7.29 (t, J=9.4 Hz, 1H), 6.70 (dd, J=8.9, 3.0 Hz, 1H), 6.07 (br. s, 1H), 5.50 (br. s, 1H), 5.35 (br. s, 1H), 4.26 (br. s, 1H), 4.03 (m, 2H), 3.92 (d, J=11.4 Hz, 1H), 3.68 (d, J=11.5 Hz, 1H), 3.61 (t, J=11.8 Hz, 1H), 3.41 (m, 1H), 2.24 (d, J=11.2 Hz, 1H), 1.81 (m, 1H), 1.49 (s, 9H), 1.35 (d, J=6.9 Hz, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=O)(C)(C)C.CC(C=C)=[O:18].C(Cl)(Cl)[Cl:22]>>[ClH:22].[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([CH3:15])[N:11]1[OH:18]
Reactant: ClC(Cl)Cl
Reactant: C=CC(C)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Product: C[C@@H]1CNC[C@H](C)N1O
Product: Cl

Procedure:
Cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.00 g; prepared according to the method E. Jon Jacobson et. al.: J. Med. Chemistry. 1999, Vol. 42, 1123-144) in 47 mL chloroform was treated with methylvinylketone (1.7 mL) at room temperature and heated at reflux for two days. The reaction was then concentrated, diluted with THF and heated at reflux for 1 day before purifying by column chromatography (0 to 10% MeOH/DCM) to afford 0.865 g of the title compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 1.08 (d, 2H, J=6.07 Hz), 1.47 (s, 9H), 2.17 (s, 3H), 2.52 (m, 6H), 3.10 (m, 2H), 2.86 (bs, 2H); 13C NMR (CDCl3, 75 MHz) 17.6 (2C), 28.62 (5C), 30.8, 37.34, 42.46, 53.57 (4C), 79.85, 154.49, 208.29.
Reaction SMILES: COC1C=[C:5]([CH:9](C)[CH2:10][CH2:11][C:12](=[O:15])C=C)[CH:6]=[CH:7]C=1.CCC(=[O:24])CCCC>[OH-].[K+]>[CH2:6]([CH:5]1[C:9](=[O:24])[CH2:10][CH2:11][C:12]1=[O:15])[CH3:7]
Reactant: CCCCC(=O)CC
Reactant: C=CC(=O)CCC(C)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and 1-diethylamino-6-)m-methoxypheyl)heptan-3-one (10 g, obtained by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (7g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes or ether and benzene (50 cc). Wash the solution with 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g); infrared absorption peak at 5.80 μ.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[CH:8]=2)=[O:4].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:16])[CH:8]=2)=[O:4]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2[nH]1
Solvent: CO
Product: COC(=O)c1cc2ccc(C(=O)NCCN3CCOCC3)cc2[nH]1
Yield: 78 %

Procedure:
2-(Methoxycarbonyl)indole-6-carboxylic acid was coupled with 4-(2-aminoethyl)-morpholine by the method described above to give 2-(methoxycarbonyl)-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide as a white powder (78%), mp 226-227.5° C. (MeOH). 1H NMR [(CD3)2SO] δ12.24 (s, 1H, indole NH), 8.42 (t, J=5.6 Hz, 1H, amide NH), 7.97 (s, 1H, H-3 or H-7), 7.71 (d, J=8.4 Hz, 1H, H-4), 7.56 (dd, J=8.4, 1.5 Hz, 1H, H-5), 7.20 (s, 1H, H-3 or H-7), 3.90 (s, 3H, CO2Me), 3.58 (t, J=4.6 Hz, 4H, CH2O), 3.41 (q, J=6.5 Hz, 2H, CONHCH2), 2.48 (t, J=7.0 Hz, 2H, CONHCH2CH2), 2.42 (t, J=4.1 Hz, 4H, NCH2CH2O); 13C NMR δ166.6 (CONH), 161.5 (CO2Me), 136.7, 131.0, 129.1, 128.5 (C-2,6,8,9), 121.6, 118.9, 112.3, 107.5 (C-3,4,5,7), 66.2 (CH2O), 57.3, 53.2 (CH2N), 51.9 (OCH3), 36.6 (NHCH2). Anal. (C17H21N3O4) C,H,N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:59][N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([C:27]([N:63]5[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]5)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CCC(Nc3ncc4ncnc(Nc5ccc(F)c(Cl)c5)c4n3)CC2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorop henyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and 1-methylpiperazine. Melting point: 194°-197° C.; Rf : 0.45 (alumina; methylene chloride/methanol=10:0.3)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=N[C:26]2C=CC=C[C:25]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:47]1[CH2:52][CH2:51][CH2:50][CH:49]([C:53]([O-:55])=[O:54])[CH2:48]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:47]2[CH2:52][CH2:51][CH2:50][CH:49]([C:53]([O:55][CH2:25][CH3:26])=[O:54])[CH2:48]2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C([O-])C1CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2cnoc2-c2ccc(C)cc2)C1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to piperidine-3-carboxylate (8 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z calcd for C19H22N2O4: 342.1580, found 342.1585
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[OH-].[K+].O.[ClH:21]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[ClH:21]
Reactant: COC(=O)c1cc(Cl)cnc1-c1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Cl)cnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.500 g, 2.01 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added potassium hydroxide (0.200 g, 3.61 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-chloro-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+C11H7ClN2O2=234.9. To a solution of the bis HCl salt form of 5-chloro-2,3′-bipyridine-3-carboxylic acid (0.613 g, 2.00 mmol) and 3,4-dimethoxybenzylamine (0.367 g, 2.2 mmol) in dimethylformamide (10 mL) was added EDC (0.764 g, 4.00 mmol), HOBt (0.612 g, 4.00 mmol) and triethylamine (0.6 mL, 10 mmol) and the system was stirred in an oil bath at 100° C. for 3 h. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was then tritirated with ether to afford 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide as a bone powder. ESI+ MS [MH]+ C20H18ClN3O3=234.9. To a solution of 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide (0.600 g, 1.56 mmol) in dioxane (5.2 mL) was added 3,5-dichlorophenyl boronic acid (1.50 g, 7.82 mmol), N,N-dicylohexylmethylamine (0.368 mL, 1.72 mmol), and bis(tri-t-butylphosphine)palladium (0.023 g, 0.047 mmol) and the system was stirred at 110° C. for 20 minutes in the microwave. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The reaction mixture was filtered and purified via normal phase chromatography (0→6% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) followed by free basing with saturated sodium carbonate afforded the title compound (2-1) as a white powder. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.95 (s, 1H), 8.66-8.68 (m, 1H), 8.15 (s, 1H), 7.98-8.00 (m, 1H), 7.53-7.54 (m, 2H), 7.46-7.47 (m, 1H), 7.28-7.30 (m, 1H), 6.77 (d, J=5 Hz, 1H), 6.39-6.66 (m, 2H), 5.69 (br s, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H). HRMS [M+H] C26H21Cl2N3O3 calc'd 494.1033, found 494.1023.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([F:18])[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[S:25][C:24]([N:26]2[CH2:29][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:27]2)=[N:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:21]2[S:25][C:24]([N:26]3[CH2:29][C:28]4([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[CH2:27]3)=[N:23][N:22]=2)=[C:11]([F:18])[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(Br)s1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OCc4ccccc4)c(F)c3F)s1)C2
Temperature: 100 °C
Yield: 36.3 %

Procedure:
Nitrogen was bubbled through a stirred solution of (4-(benzyloxy)-2,3-difluorophenyl)boronic acid (356 mg, 1.349 mmol) and tert-butyl 2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (343 mg, 0.881 mmol) in dioxane (8 mL). To this solution was added Pd(PPh3)4 (52 mg, 0.045 mmol) followed by a solution of Na2CO3 (286 mg, 2.7 mmol) in water (2 mL). The reaction mixture was sealed and heated at 100° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (75 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a light orange/brown solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (169 mg, 35% yield). LC-MS: Rt 1.62 min; MS m/z 529.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.82 (m, 1H), 7.46-7.51 (m, 2H), 7.36-7.45 (m, 3H), 7.24-7.32 (m, 1H), 5.30 (s, 2H), 3.89 (s, 4H), 3.24-3.31 (m, 4H), 1.66-1.78 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 96 h
Yield: 49.7 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (0.50 g) is dissolved in 5 ml of dry THF and 0.48 g of tetra-butylammoniumfluoride hydrate and 0.4 g of pulverised molecular sieve is added and the mixture is stirred for 4 days. After column chromatography and crystallization from methanol/water and methanol, the title compound (195 mg) is isolated. Melting point: 124-128° C. 1H-NMR (CDCl3, 400 MHz): δ=5.91 (1H, m); 5.53 (1H, m); 3.67 (3H, s). 3.4 (1H, m). MS: Calculated: 414.6. Found 414.3.