Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:3]=1.[NH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][NH:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: CN(C)C(=O)CN
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(-c3ccccc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 150 °C
Yield: 89.2 %

Procedure:
A mixture of 4-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-pyrimidine (15 g), 2-amino-N,N-dimethylacetamide (8.2 g) and triethyl-amine (5.4 g) is heated at 150° C. under reflux for 2 hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to give the desired compound (16 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:37][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 33.8 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.021 g (0.23 mmole) of N,N-dimethyl-ethane-1,2-diamine, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.028 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide (I-52) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O.ClCCl>[Br:17][CH2:18][CH2:19][CH2:20][O:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CO)c(=O)c(OCCCBr)c1
Temperature: 80 °C
Yield: 14 %

Procedure:
60% oily sodium hydride (292, mg, 7.3 mmol) in small portions were added to a solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.29 g, 6.64 mmol) in dimethylformamide (5 ml) with stirring. After addition of 1,3-dibromopropane (1.35 ml, 13.3 mmol), the solution was heated at 80° C. for 4 hours. The solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 293 mg of 2-(3-bromopropoxy)-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a pale yellow crystal (yield: 14%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.Cl>O.C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NCc1ccc(N)cc1
Yield: 79.5 %

Procedure:
To a suspension of 25.9 g (113 mmol, 1.0 equiv.) of N-[(4-nitrophenyl)methyl]methanesulfonamide in 113 mL of 1N HCl (113 mmol, 1.0 equiv.), 113 mL of water and 225 mL of ethanol was added 5.18 g of 10% palladium on carbon. This mixture was hydrogenated in a Parr apparatus at 60 psi for sixteen hours. The mixture was filtered through Celite. The ethanol was removed in vacuo and the pH adjusted to 9, at which point the product had precipitated. The precipitate was isolated by filtration and dried in vacuo to yield 18.0 g (80%) of N-[(4-aminophenyl)methyl]-methanesulfonamide.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>O.C(O)(=O)C>[N:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:2]([NH2:3])=[O:1])=[CH:11][CH:10]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A solution of sodium cyanate (0.26 g) in water (30 ml) was added over 10 minutes to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.50 g) in a mixture of acetic acid (20 ml) and water (30 ml). The solution was stirred for 2 hours, allowed to stand for 18 hours and then evaporated. The residue was triturated with water and filtered. The solid was crystallised from N,N-dimethylformamide to give the title compound (0.27 g), m.p. above 250° C. Found: C,64.17; H,6.42; N,23.32. C16H19N5O requires: C,64.62; H,6.44; N,23.55%.
Reaction SMILES: [CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4OCCCO4)=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.[BH3-]C#N.[Na+]>C1COCC1.C(OCC)C.C(N(CC)CC)C>[CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][S:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][N:32]4[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]4)=[CH:17][CH:18]=3)=[CH:9][C:8]=2[C:27]([F:30])([F:28])[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CNC1
Reactant: FC(F)(F)c1cc(CSc2ccc(C3OCCCO3)cc2)ccc1C1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccc(SCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[4-(4-cyclohexyl-3-trifluoromethyl-benzylsulfanyl)-phenyl]-[1,3]dioxane (90 mg, 0.2 mmol) in THF (10 mL), is added aqueous HCl (2N, 0.7 mL). The solution is stirred at room temperature for 4 h. The solution is diluted with diethyl ether (30 mL), and washed with saturated aqueous NaHCO3 (3×10 mL). The organic layer is washed with saturated aqueous NaCl, dried over Na2SO4, and partially concentrated followed by dilution with MeOH (10 mL). To the resulting solution is added triethyl amine (0.5 mL) and azetidine-3-carboxylic acid (46 mmol, 0.4 mmol). The resulting mixture is stirred at 50° C. for 30 min. The reaction is cooled to room temperature and NaCNBH3 (63 mg, 1 mmol) is added. The resulting mixture is stirred for 30 min followed by concentration to dryness. The crude product is purified by preparative RP LC-MS to give 1-[4-(4-cyclohexyl-3-trifluoromethyl-benzylsulfanyl)-benzyl]-azetidine-3-carboxylic acid as a colorless oil. 1HNMR (400 MHz, CD3OD) δ7.55–7.54 (m, 2H), 7.52–7.35 (m, 5H), 4.39 (s, 2H), 4.35 (m, 4H), 4.17 (s, 2H), 3.68 (tt, 1H), 2.90 (tt, 1H), 1.87–1.75(m, 5H), 1.72–1.48 (m, 5H); MS (ES+): (464.2, M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20](O)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.Cl.[OH:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20]([N:28]3[CH2:29][CH:26]([OH:25])[CH2:27]3)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2)N1CC(O)C1
Temperature: 75 °C
Yield: 66 %

Procedure:
Example 1 (100 mg, 0.23 mmol) was added to a suspension of 3-hydroxyazetidine hydrochloride (50 mg, 0.46 mmol), HATU (132 mg, 0.35 mmol), and N-methylmorpholine (0.13 mL, 1.15 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 5 hours and then concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified via preparative HPLC (25/70 acetonitrile/water) to give 74 mg (76%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.59 (dd, 1H, J=10.6, 1.8 Hz), 7.72 (dd, 1H, J=8.6, 1.7 Hz), 6.88 (t, 1H, J=8.3 Hz), 5.32 (s, 1H), 4.31-4.48 (m, 2H), 4.05-4.15 (m, 1H), 3.98 (t, 2H, J=6.6 Hz), 3.83-3.94 (m, 1H), 3.72 (m, 1H), 3.50 (m, 1H), 2.89-3.06 (m, 2H), 2.06-2.12 (m, 2H). MS (ES) [m+H] calc'd for C18H16F2IN3O3, 488. found 488.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([NH2:58])[CH:53]=[C:52]2[CH3:59]>CN(C=O)C.O.CCOC(C)=O>[F:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([NH:58][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH:53]=[C:52]2[CH3:59]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)cc12
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (335 mg, 1.56 mmol), HOTT (638 mg, 1.72 mmol), and DIPEA) (700 μL, 4.01 mmol in DMF (6 mL) is stirred stirred at rt under N2 for 20 min. 5-Fluoro-3-methyl-indol-1-ylamine (241 mg, 1.47 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60% EtOAc in heptane to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)amide (193 mg, 36%) as a solid. MS: 362 (M+H). 1H NMR (300 MHz, CDCl3): δ 10.41 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.48-8.45 (m, 1H), 7.86 (t, 1H), 7.40-7.36 (m, 1H), 7.24-7.20 (m, 2H), 7.05-7.01 (m, 2H), 2.82 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:9][CH2:8]1)C.[Li+].[BH4-].Cl>C1COCC1>[C:18]([O:17][C:15](=[O:16])[N:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH2:12][CH2:11]1)[CH3:14])([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)CC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCO)CC1
Temperature: 0 °C

Procedure:
A solution of 6 g (19.26 mmol) trans-3-[4-(tert-Butoxy carbonyl methyl-amino)-cyclohexyl]-acrylic acid ethyl-ester and 600 mg of Pd/C (10%) was stirred over H2-atmosphere for 20 h. After filtration of the solution, the methanol was evaporated under reduced pressure to yield 5.82 g of clean trans-3-[4-(tert-Butoxycarbonyl methyl-amino)cyclohexyl]-propanoic acid ethyl-ester. To a solution of this ester in 60 ml of THF was added 917 mg (40 mmol) LiBH4. The solution was refluxed for 8 h and then cooled with an ice-bath to 0° C. At this temperature was dropped slowly 1N HCl to the reaction-mixture to destroy excess of LiBH4. The reaction-mixture was diluted with Et2O and then washed with water: The organic layers were evaporated to dryness to yield 3.39 g (73%) of clean trans-[4-(3-Hydroxy-propyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 271 (M).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[C:33]([O:34]COCC[Si](C)(C)C)=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[O:22][CH2:23][C:24]2[C:33]([OH:34])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cc3ccccc3cc2OCOCC[Si](C)(C)C)C1
Agent: Cl
Product: Oc1cc2ccccc2cc1COC1CNCCC1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Examples 3 and 5(g), by cleaving off the two protecting groups with methanolic hydrochloric acid from tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate there was obtained (3RS,4RS)-4-(4-fluorophenyl)-3-(3-hydroxy-naphthalen-2-yl-methoxy)-piperidine as a colourless solid, MS: 351 (M)+.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N+:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:22][CH2:21]1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture 3,3-tetramethyleneglutarimide (16.7 g., 0.1 mole), 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide (29.9 g., 0.1 mole) and potassium carbonate (16.6 g., 0.12 mole) in 190 ml. of dimethylformamide is maintained at 150°-155° C. for a reaction period of 24 hours and then evaporated to dryness under reduced pressure. The resulting solid is triturated with 90 ml. of water, taken up in 10% hydrochloric acid and filtered. The acid filtrate is made basic with 10% aqueous sodium hydroxide and precipitated free base collected and dried to provide 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione.
Reaction SMILES: [CH2:1]([C@:8]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]([O:19]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29].COC(C)(C)C>CO>[CH2:1]([C@:8]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]([NH2:29])=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@@](Cc3ccccc3)(NC(=O)OC(C)(C)C)C(=O)N21
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Reaction time: 8 h

Procedure:
A mixture of 170 mg of methyl (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate and 10 ml of a 7N NH3 solution in methanol is left to stand at room temperature overnight. The volatile constituents are stripped off in vacuo, and the residue is stirred with tert-butyl methyl ether, and the solid is filtered off with suction and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]=[CH:14][O:15]C.[Na+].[I-].C[Si](Cl)(C)C>CC#N>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5]([CH2:13][CH:14]=[O:15])=[CH:6][CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: COC=Cc1cccc([N+](=O)[O-])c1C(=O)OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1c(CC=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(2-methoxy-vinyl)-6-nitro-benzoic acid methyl ester (Step A, 3.33 g, 14.1 mmol, 1.0 eq) and CH3CN (20 mL) was added NaI (2.3 g, 15.5 mmol, 1.1 eq) and TMSCl (2 mL, 15.5 mmol, 1.1 eq). The reaction was stirred at RT for 4 h, then quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give a red-orange oil. Purification by silica flash chromatography (0-30% EtOAc:hexane) gave the desired compound as an orange oil.
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[Br:16])=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:16][C:9]1[C:8]2[N:7]3[CH2:17][CH2:18][NH:19][C:20](=[O:22])[C:6]3=[CH:14][C:13]=2[CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2n1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a stirred solution of ethyl 7-bromo-1-(2-(tert-butoxycarbonylamino)ethyl)-5-fluoro-1H-indole-2-carboxylate (step A) (1.43 g, 3.33 mmol) in dichloromethane (15.2 ml) was added drop wise at 0° C. trifluoroacetic acid (4.79 g, 3.23 ml, 42.0 mmol). Afterwards the solution was allowed to stir for 15 min at 0° C., and for 30 min at room temperature. The reaction mixture was evaporated and the remaining material was solved in methanol (15.2 ml). Potassium carbonate (1.83 g, 13.3 mmol) was added and the mixture was allowed to stir at room temperature for 17 h. The mixture was evaporated, water (50 ml) was added and the mixture was extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product (0.86 g) was purified by trituration with dichloromethane (3 ml) and heptane (15 ml) to yield the title compound as an off-white solid (0.85 g, 90%), MS (ISN) m/z=283.2 [(M+H)+], mp 253.5° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC(=O)[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][C:20]=2[CH3:35])[CH2:15]1)(C)(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:35][C:20]1[CH:21]=[C:22]([S:25]([C:28]2[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:23]=[CH:24][C:19]=1[CH:16]1[CH2:17][CH2:18][N:14]([CH3:13])[CH2:15]1
Reactant: Cc1cc(S(=O)(=O)c2cccc(O)c2)ccc1C1CCN(CC(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)c2cccc(O)c2)ccc1C1CCN(C)C1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of LAH (1.0 M in THF, 0.51 mL) was added to a solution of {3-[4-(3-hydroxy-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid tert-butyl ester (85 mg, 0.2036 mmol) in THF (1 mL). The reaction mixture was stirred at reflux for 2 hours, it was cooled to room temperature and Na2SO4. 10H2O was added. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 42 mg of 3-[3-methyl-4-(1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-phenol as a white foam: MS (M+H)=332.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[CH2:27]2)=[N:24][CH:25]=1>>[C:32]([N:31]([CH3:35])[CH:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=2)[CH2:27]1)(=[O:34])[CH3:33]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(=O)N(C)C1CCN(c2ccc(N)cn2)C1
Product: CC(=O)N(C)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide. LCMS calcd for C23H22F3N5O3 (m/e) 473, obsd 474 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[O:19][C:20]([C:23]3[S:24][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=3)=[N:21][N:22]=2)=[CH:13][C:12]=1[CH3:32])[CH2:3]OS(C)(=O)=O.[NH3:33]>C1COCC1.CO>[NH2:33][CH2:3][CH:2]([OH:1])[CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[O:19][C:20]([C:23]3[S:24][C:25]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=3)=[N:21][N:22]=2)=[CH:13][C:12]=1[CH3:32]
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)COS(C)(=O)=O
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CN

Procedure:
A solution of methanesulfonic acid 2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl ester (220 mg, 0.458 mmol) in THF (10 mL) and 7 N NH3 in methanol (10 mL) is stirred at 65° C. for 15 h. The solvent is evaporated and the residue is separated by chromatography on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give 1-amino-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (110 mg) as a yellow oil; LC-MS: tR=0.83 min, [M+1]+=402.48.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:21][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:13]
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccccc1Br
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of 3-(2-bromophenyl)-propylamine (6.9 g, 30 mmol), 2-bromomethyl-benzoic acid methyl ester (6.42 g, 30 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 2 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(2-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (5.7 g, 58%). GC/MS gave: m/z (rel.int.) 331 (M+, 3), 329 (M+, 3), 250 (42), 147 (82), 146 (100) 119 (27), and 91 (47). 1H NMR (300 MHz, CDCl3): δ 2.00 (dt, 2H), 2.80 (t, 2H), 3.74 (t, 2H), 4.40 (s, 2H), 7.04 (dt, 1H), 7.19-7.27 (m, 3H), 7.43-7.53 (m, 3H), 7.76 (dd, 1H). 13C NMR (300 MHz, CDCl3): δ 28.7, 33.7, 42.1, 50.0, 122.8, 123.8, 124.4, 127.7, 127.9, 128.1, 130.6, 131.3, 132.9, 133.1, 140.8, 141.3, 168.7.