Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH:19]([C:21]1[CH:22]=[C:23]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[CH:24]=[CH:25][CH:26]=1)=[CH2:20].I[C:37]1[C:45]2[C:40](=[CH:41][C:42]([CH:46]=[O:47])=[CH:43][CH:44]=2)[N:39]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:38]=1>>[CH3:35][N:32]1[CH2:31][CH2:30][N:29]([C:27]([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)/[CH:19]=[CH:20]/[C:37]2[C:45]3[C:40](=[CH:41][C:42]([CH:46]=[O:47])=[CH:43][CH:44]=3)[N:39]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:38]=2)=[O:28])[CH2:34][CH2:33]1
Reactant: C=Cc1cccc(C(=O)N2CCN(C)CC2)c1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: CN1CCN(C(=O)c2cccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)c2)CC1

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing 1-[(3-ethenylphenyl)carbonyl]-4-methylpiperazine (76 mg, 0.33 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a colorless material (30.1 mg, 24%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1H), 8.27 (s, 1H), 7.80 (m, 1H), 7.71 (s, 1H), 7.65 (d, J=16.6 Hz, 1H), 7.56-7.60 (m, 1H), 7.57 (s, 1H), 7.48-7.55 (m, 2H), 7.35 (d, J=7.28 Hz, 1H), 5.86 (s, 2H), 3.69-3.90 (m, 2H), 3.63 (t, J=7.91 Hz, 2H), 3.43-3.56 (m, 2H), 2.40-2.64 (m, 4H), 2.35 (s, 3H), 0.88 (t, J=7.91 Hz, 2H), −0.09 (m, 9H); MS ESI 505.4 [M+H]+, calcd for [C28H36N4O3Si+H]+ 505.7.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:20]([OH:25])[OH:21])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 23 (27.78, 0.14 mol), n-butyllithium (14 cm3, 10.0M in hexanes, 0.14 mol) and triisopropyl borate (52.7 g, 0.28 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [ClH:1].[N:2]1([C:7]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:21])[C:13](=[O:20])[N:14]3[CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[N+:22]([O-])([O-:24])=[O:23].[K+]>S(=O)(=O)(O)O>[ClH:1].[N:2]1([C:7]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:21])[C:13](=[O:20])[N:14]3[CH2:17][CH2:18][CH3:19])=[CH:9][C:8]=2[N+:22]([O-:24])=[O:23])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCCn1c(=O)c(=O)[nH]c2ccc(-n3ccnc3)cc21
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 1 g of 7-(1-imidazolyl)-1-n-propylquinoxaline-2,3-(1H,4H)-dione hydrochloride in 8 ml of sulfuric acid was added 0.4 g of potassium nitrate, and the mixture was stirred overnight. The reaction mixture was poured in ice-water and adjusted to pH 7. The resulting crystals were recrystallized from 1N-hydrochloric acid to provide 0.9 g of 7-(1-imidazolyl)-6-nitro-1-n-propylquinoxaline-2,3-(1H,4H)-dione hydrochloride.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH:25]1[O:49][CH:26]1[CH2:27][O:28][CH2:29][CH:30]1O[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]CCC)CCCCCCCCCCCCCCC>O1CCCC1>[CH2:1]([NH:8][CH2:25][CH:26]([OH:49])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCC1OC1COCC1OC1CCCCCCCCCCCCCCCC
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(O)CNCc1ccccc1

Procedure:
A mixture of 24.4 g of benzylamine, 100 cc. of tetrahydrofurane and 34 g of hexadecyl-2.3-epoxypropylether is refluxed for 8 hours and the solvent is evaporated in a vacuo. The residue is recrystallized from hexane.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:18][C:4]2([CH2:7][CH:6]([C:8]([O:10]CC3C=CC=CC=3)=[O:9])[CH2:5]2)[CH2:3]1>[Pd].CCOC(C)=O>[F:1][C:2]1([F:19])[CH2:3][C:4]2([CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]2)[CH2:18]1
Reactant: O=C(OCc1ccccc1)C1CC2(C1)CC(F)(F)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CC2(C1)CC(F)(F)C2
Reaction time: 2 h

Procedure:
A stirred suspension of 10% Pd—C (40.6 mg) in an EtOAc (10 mL) solution of benzyl 6,6-difluorospiro[3.3]heptane-2-carboxylate (203 mg) was hydrogenated under balloon pressure for 2 h. The suspension was filtered and the filtrate was evaporated to dryness to afford Cap-13 as a clear viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.18-3.08 (m, 1H), 2.69-2.55 (m, 4H), 2.52-2.37 (m, 4H).
Reaction SMILES: C([O:9][CH2:10][C:11]1([CH2:23][O:24]C(=O)C2C=CC=CC=2)[CH2:13][CH:12]1[CH2:14][N:15]1[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]1=[O:17])(=O)C1C=CC=CC=1>Cl>[OH:24][CH2:23][C:11]1([CH2:10][OH:9])[CH2:13][CH:12]1[CH2:14][N:15]1[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]1=[O:17]
Reactant: O=C(OCC1(COC(=O)c2ccccc2)CC1Cn1ccc(=O)[nH]c1=O)c1ccccc1
Agent: Cl
Product: O=c1ccn(CC2CC2(CO)CO)c(=O)[nH]1
Reaction time: 5 h

Procedure:
A suspension of 3.62 mmoles of 1-[2,2-bis(benzoyloxymethyl)-1-cyclopropylmethyl]uracil in 178 ml of 2.5N HCl is stirred at 100° for about 5 hours. The reaction mixture is concentrated to a residual semi-solid which is triturated with three 20 ml portions of Et2O and dried, and the residue is dissolved in 5 ml of water and neutralized (pH 7) with 2N NaOH. The solid separates and is removed and dried, and the filtrate is concentrated to dryness. The solids are then combined, dissolved in a small amount of CHCl3 -MeOH (1:1) and put on five 2000 micron preparative TLC plates which are developed in CMW (70:30:3). The product bands (Rf 0.3) are eluted with CHCl3 -MeOH (3:2) and when concentrated yield the titled product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1>CO>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCN(C(=O)CCl)CC2)cc1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Solvent: CO
Product: Cc1ccc(CC2CCN(C(=O)CNc3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-methyl-benzyl)-piperidin-1-yl]-ethanone (Example 227a) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 206. Melting Point: 212-215° C. (methanol)
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][NH:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1SC(=S)N([CH:27]=[O:28])N=1>CC(C)=O>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:27]=[O:28])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](CNOC1CCCCO1)CC1CCCC1
Reactant: Cc1nn(C=O)c(=S)s1
Solvent: CC(C)=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reaction time: 0.17 h
Yield: 115.7 %

Procedure:
To a solution of (2R)-3-cyclopentyl-2-{[(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (97.05 g, 358 mmol) in acetone (1.1 L) at room temperature was added 5-methyl-2-thioxo-[1,3,4]thiadiazole-3-carbaldehyde (57.3 g, 358 mmol) (Tetrahedron Lett. 1985, 26, 3703-3706). When the reaction was deemed complete, the acetone was removed in vacuo. The residue was suspended in a mixture of hexanes (320 mL) and methyl-t-butyl ether (180 mL), then sonicated. After 10 min, the white solid (presumably 5-methyl-3H-[1,3,4]thiadiazole-2-thione) was filtered off, and the filtrate was evaporated in vacuo to give (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid as a pale yellow gum (124 g, >100%). NMR shows the product contains a small amount of MTBE and 5-methyl-3H-[1,3,4]thiadiazole-2-thione.
Reaction SMILES: Br[C:2]#[N:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1>CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[O:13][C:2]([NH2:3])=[N:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: NNC(=O)Cc1ccc(F)cc1
Solvent: CO
Product: Nc1nnc(Cc2ccc(F)cc2)o1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Solid BrCN 13.37 g (130 mmol, 1.1 eq.) was added in one portion into ice-cooled slurry of (4-Fluoro-phenyl)-acetic acid hydrazide (19.85 g, 118 mmol) and KHCO3 14.77 g (147.5 mmol, 1.25 eq.) in MeOH (150 mL) in a 1L flask. (Followed by MeOH 10 mL to wash the funnel). The mixture was stirred on ice bath at 0-5° C. for 2 hours in a loose-capped flask, then the bath allowed to melt gradually and then the mixture was stirred at 5 to 20° C. overnight (17 hrs). The reaction mixture was diluted with water (200 mL), stirred for 1 hour in an open flask, then cooled on ice bath. The precipitate was collected by filtration, washed with water and dried on highvac. [1st fraction]The supernatants were concentrated on rotavap form warm (40° C.) water bath to remove all MeOH and some water. The obtained slurry was cooled to room temperature, the precipitate was collected by filtration, washed with water and dried on highvac. [2nd fraction]. Combined yield: 20.836 g (91.5%) of a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23]([NH:25][C@H:26]3[CH2:31][C@H:30]4[CH2:32][C@H:28]([C:29]4([CH3:34])[CH3:33])[C@@H:27]3[CH3:35])=S)=[CH:17][CH:18]=2)[N:13]=[CH:12]1.N=C=N>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N:22]=[C:23]=[N:25][C@H:26]3[CH2:31][C@H:30]4[CH2:32][C@H:28]([C:29]4([CH3:34])[CH3:33])[C@@H:27]3[CH3:35])=[CH:17][CH:18]=2)[N:13]=[CH:12]1
Reactant: C[C@@H]1[C@@H](NC(=S)Nc2ccc3c(=O)n(CCc4ccc(Cl)cc4Cl)cnc3c2)C[C@H]2C[C@@H]1C2(C)C
Agent: N=C=N
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](N=C=Nc2ccc3c(=O)n(CCc4ccc(Cl)cc4Cl)cnc3c2)C[C@H]2C[C@@H]1C2(C)C

Procedure:
N-{3-[2-(2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]thiourea was gently stirred with Argonaut PS-Carbodiimide (1.5 eq) for 15 hours in THF. The resin was filtered off and the solution of carbodiimide B was diluted to a known volume to give a solution of known molarity.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[SH:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].Cl.CN(C)CCCN=C=NCC>ClCCl>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:15](=[O:17])[C@H:2]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2)[CH:12]=1)[CH3:1]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OCCCCS
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)SCCCCO)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of naproxen (5.03 g, 21.9 mmol), 4-mercapto-1-butanol (2.32 g, 21.9 mmol) and N,N-dimethylaminopyridine (DMAP) (0.534 g, 4.37 mmol) in dichloromethane (200 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC) (5.03 g, 26.2 mmol) as a solid, in portions. The reaction mixture was stirred for 3 hours at room temperature, then partitioned between dichloromethane and water, and the water layer was washed with more dichloromethane. The combined organic layer was washed with water and brine, then dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 50% ethyl acetate/hexane. The appropriate fractions were combined, and the solvent removed by rotary evaporation to give an oil, 2.647 g, which contained 19% 4-mercapto-1-butanol by weight (product weight 2.07 g, 6.5 mmol, 30% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=2.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 4.02 (q, J=7.1 Hz, 1H), 3.92 (s, 3H), 3.61-3.64 (m, 2H), 2.87 (m, 2H), 1.61 (d, J=7.1 Hz, 3H), 1.59 (m, 2H), 1.41 (m, 2H); mass spectrum (API-TIS) m/z 319 (M+H+), 336 (M+18+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])=[C:20]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:19]=[CH:18][C:12]=1[CH:13]=[CH:14][C:15]([OH:17])=[O:16])(=[O:4])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[C:46]1([CH3:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])=[C:20]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:19]=[CH:18][C:12]=1[CH:13]=[CH:14][C:15]([O:17][C:49]1[CH:50]=[CH:51][C:46]([C:52]2[CH:20]=[CH:21][C:11]([O:16][C:15](=[O:17])[CH:14]=[CH:13][C:12]3[CH:18]=[CH:19][C:20]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])=[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])[C:11]=3[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:13]=2)=[CH:47][CH:48]=1)=[O:16])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCOc1ccc(C=CC(=O)O)c(OCCCCOC(=O)C=C)c1OCCCCOC(=O)C=C
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C=CC(=O)Oc2ccc(-c3ccc(OC(=O)C=Cc4ccc(OCCCCOC(=O)C=C)c(OCCCCOC(=O)C=C)c4OCCCCOC(=O)C=C)cc3)cc2)c(OCCCCOC(=O)C=C)c1OCCCCOC(=O)C=C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Into a three-neck flask, 2,3,4-tri(4-acryloyloxy-butyloxy)cinnamic acid (10.0 g), thionyl chloride (6.1 g), dimethylformamide (0.01 g) and 30 mL of toluene were added and stirred at 40° C. for 30 minutes. After cooling, toluene and excess thionyl chloride were removed by distillation and then 100 ml of tetrahydrofuran was added. To this reaction solution, 4,4′-dihydroxybiphenyl (1.6 g) was added and after cooling to 5° C., triethylamine (2.8 mL) was added dropwise. Subsequently, 4-dimethylaminopyridine (0.1 g) was added and after heating to 25° C., the solution was stirred for 5 hours. The resulting reaction solution was added to water (500 mL) and crystals precipitated were collected by filtration. The obtained crystals were dissolved in dimethylacetamide (20 mL), triethylamine (2.8 mL) was added thereto and the resulting solution was stirred at 60° C. for 1 hour. After cooling, the reaction solution was extracted with ethyl and washed with water. The extract was concentrated and then purified by column chromatography to obtain the titled compound (9.5 g). Yield: 85%. The NMR spectrum of m-40 obtained is shown below.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Br:15])[CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2)(=O)C.C[O-].[Na+]>CO>[Br:15][C:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([OH:4])[CH:14]=1
Reactant: CC(=O)Oc1cc(Br)c2c(c1)CCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1cc(Br)c2c(c1)CCCC2

Procedure:
Compound of step b) (6.1 g, 22.66 mmol) is added to MeOH (200 ml) at RT. 1N sodium methoxide in methanol (22.7 ml) is stirred for 15 min. Amberlite IR-120 (H+-form) is added to the mixture until the reaction mixture becomes neutral. The ion exchanger is filtered off, the solvent is evaporated and the crude product is isolated without any further purification as a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.B([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][N:54]2[CH2:59][CH2:58][S:57](=[O:61])(=[O:60])[CH2:56][CH2:55]2)=[CH:49][CH:48]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[O:61]=[S:57]1(=[O:60])[CH2:58][CH2:59][N:54]([CH2:53][C:50]2[CH:51]=[CH:52][C:47]([C:21]3[N:29]4[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]5[CH:32]=[CH:33][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]6)=[CH:35][CH:36]=5)=[N:28]4)=[CH:23][CH:22]=3)=[CH:48][CH:49]=2)[CH2:55][CH2:56]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(CN6CCS(=O)(=O)CC6)cc5)n4n3)cc2)CC1
Temperature: 90 °C
Yield: 100 %

Procedure:
Palladium acetate (25.5 mg, 0.114 mmol) and triphenylphosphine (65.6 mg, 0.250 mmol) were dissolved in 1,4-dioxane (2.00 mL) and the mixture was purged with nitrogen for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (110 mg, 0.284 mmol), 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide (306 mg, 1.14 mmol), N,N-dimethylformamide (2.00 mL) and 1.50 M sodium carbonate in water (0.379 mL, 0.568 mmol) were added. The reaction mixture was heated at 90° C. overnight and then partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was washed with water (50 mL) and brine (25 mL) and then dried over Na2SO4. Purification by silica gel chromatography using a gradient of 0-10% MeOH/DCM as the eluting solvent to obtain the title compound as a yellow-brown foam (151 mg, 100%). LCMS (m/e) 532 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.13 (d, 2H, J=7.4 Hz), 7.54 (d, 2H, J=7.8 Hz), 7.41 (d, 2H, J=7.8 Hz), 7.02-6.90 (m, 3H), 6.84-6.78 (m, 1H), 6.70-6.62 (m, 1H), 3.73 (s, 2H), 3.23-3.15 (m, 4H), 3.13-3.00 (m, 8H), 2.66-2.57 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[CH3:22]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[CH3:22]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cc(C)c2cccc(Br)c2n1
Product: Cc1cc(C)c2cccc(Nc3c(C)cccc3C)c2n1
Yield: 46 %

Procedure:
Repeat the procedure of Example 1 except use 2,6-dimethylaniline instead of 2,6-diisopropylaniline and 8-bromo-2,4-dimethylquinoline instead of 8-bromoquinoline to give purified (4) in 46% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To a solution of 742 mg (2.5 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 50 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg (56.7%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1020.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH3:25])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:28])([F:29])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:25])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed methanol (5 mL), methyl 4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoate (60 mg, 0.13 mmol, 1.00 equiv), 15% NaOH (2 mL). The resulting solution was stirred for 2 h at 60° C. in an oil bath. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 3-4 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×5 mL of Brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 57 mg (98%) of 4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[C:18]1(/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:4]([C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:26]([CH:25]=[CH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)/C=C/C=C/c1ccccc1
Reactant: C=CCN[C@@H](C)c1ccccc1
Agent: [Li]CCCC
Product: C=CCN([C@@H](C=Cc1ccccc1)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Yield: 97.6 %

Procedure:
The procedure of Example 1 was repeated using (S)-N-allyl-α-methylbenzylamine (2) (0.840 g, 5.22 mmol), 1.6M butyllithium (2.16 ml, 4.17 mmol) and t-butyl 5-phenyl-(E,E)-pentadienoate (19) (0.800 g, 3.48 mmol) as the Michael acceptor. Flash chromatography on silica gel [ethyl acetate/petroleum ether (1:19)] afforded the title compound (20) as a colourless oil (1.33 g, 98%). δH (200 MHz; CDCl3) 7.48-7.21 (10H, m, Ph), 6.48 (1H, d, J=16.0, PhCH=CH), 6.25 (1H, dd, J=16.0 and 7.4, PhCH=CH), 5.85 (1H, m, NCH2CH=CH2), 5.15 (1H, app. dd, J=17.3 and 1.6, trans NCH2CH=CH), 5.07 (1H, app. dd, J=10.3 and 1.5, cis NCH2CH=CH2), 4.09 (2H, m, PhCHCH3 and PhCH=CHCH), 3.22 (2H, d, J=6.1, NCH2), 2.56 (1H, dd, J=14.3 and 6.6, CH2CO2), 2.42 (1H, dd, J=14.3 and 8.2, CH2CO2), 1.43 (3H, m, PhCHCH3), 1.42 (9H, s, (CH3)3C).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:37])[CH2:10][CH2:11][CH:12]=[C:13]1[CH:18]2[CH:16]3[CH:17]2[CH2:19][CH:14]1[CH:15]3[C:20]1[NH:28][C:27]2[C:26](=[O:29])[N:25]([CH2:30][CH2:31][CH3:32])[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22]=2[N:21]=1>CCO.Cl.[Pt]>[CH3:37][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][CH:13]1[CH:18]2[CH:16]3[CH:17]2[CH2:19][CH:14]1[CH:15]3[C:20]1[NH:28][C:27]2[C:26](=[O:29])[N:25]([CH2:30][CH2:31][CH3:32])[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22]=2[N:21]=1
Reactant: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=CCCN(C)C)C53)nc2n(CCC)c1=O
Agent: [Pt]
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4CCCN(C)C)C53)nc2n(CCC)c1=O

Procedure:
8-[5-(3-Dimethylamino-propylidene)-tricyclo[2.2.1.02,6]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; compound with trifluoro-acetic acid was hydrogenated under 60 psi using Pt/C 5% in EtOH (10 ml) and 1 ml conc. HCl overnight. Catalyst was filtered and solvent was removed under reduced pressure. Crude product was purified by HPLC Yield 30 mg. Mass (ES+ 414).