Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH2:10][CH2:9]1.[C:26]([N:34]1[CH2:39][CH2:38][C:37]([CH2:46][CH:47]=O)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:36][CH2:35]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].C([O-])=O>C(Cl)Cl>[C:26]([N:34]1[CH2:35][CH2:36][C:37]([CH2:46][CH2:47][N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:15]=3)[CH2:12][CH2:13]2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1cncc(Cc2noc(C3CCNCC3)n2)c1
Reactant: O=CCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(CCN2CCC(c3nc(Cc4cccnc4)no3)CC2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
The TFA salt of 3-[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]pyridine (27 mg, 0.076 mmol) was combined with (1-benzoyl-4-phenylpiperidin-4-yl)acetaldehyde (21 mg, 0.069 mmol) in 2 mL DCM and treated with NaBH(OAc)3 (43 mg, 0.203 mmol) at ambient temperature with agitation for 18 h. 1 mL of saturated aqueous NaHCO3 was added and agitated 1 h. The organic phase was separated and concentrated. The crude product was purified by HPLC (METHOD) to give 3-[(5-{1-[2-(1-benzoyl-4-phenylpiperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol-3-yl)methyl]pyridine (14.2 mg, 0.024 mmol, 34%) as the formate salt. 1H NMR (300 MHz, CD3OD) δ 8.52-8.44 (m, 2H), 7.80 (d, 1H, J=7.9 Hz), 7.48-7.38 (m, 10H), 7.26 (m, 1H), 4.19 (m, 1H), 4.13 (s, 2H), 3.59 (m, 1H), 3.36-3.29 (m, 3H), 3.12-3.02 (m, 3H), 2.47-1.45 (m, 13H). ES-LCMS m/z 536.25 (M+H). HRMS C33H37N5O2 m/z 536.3026 (M+H)Cal. 536.3018 (M+H)Obs..
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([O:9]C(=O)C)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O.N>P(Cl)(Cl)(Cl)=O>[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[C:5]([OH:9])[CH:6]=2
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: CC(=O)Oc1cnc(N)c(N)c1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncc(O)cc2[nH]1
Temperature: 0 °C

Procedure:
0.5 g of 2,3-diamino-5-acetoxy-pyridine and 0.83 g of 2-methoxy-4-methanesulfonylamino-benzoic acid were refluxed for one hour in 20 ml of phosphorus oxychloride. The reaction mixture was combined with ice water and then ad]usted to pH 7 with concentrated aqueous ammonia. The product was then extracted with ethyl acetate and purified by column chromatography (silica gel, eluant: methylene chloride/ethanol 1:0.02 to 1:0.1). Yield: 0.06 g (6% of theory). Melting point: 225° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[N:17][CH:16]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CN(C=O)C>[Cl:21][C:18]1[N:17]=[CH:16][C:15]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6](=[O:8])[NH:7][C:2]=3[N:1]=2)=[CH:20][CH:19]=1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(Cl)nc2)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)[nH]c2nc(-c3ccc(Cl)nc3)[nH]c2c1=O
Temperature: 101 °C
Yield: 77.5 %

Procedure:
A mixture of N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide (2.47 g, 7.6 mmol), P2O5 was taken in DMF (20 ml) and heated at 100-102° C. for 30 minute. Reaction mixture was cooled to room temperature and cold water (60 ml) was added. Precipitated solid was filtered off to get 8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione as pale yellow solid (1.8 g, 77%).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[S:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:20][C:21](=O)[NH:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([O:31][CH3:32])[N:24]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:30][O:29][C:27]1[N:26]=[C:25]([O:31][CH3:32])[N:24]=[C:23]([NH:22][C:21]([NH:14][S:11]([C:10]2[C:5]3[S:4][CH2:3][CH2:2][S:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:12])=[O:13])=[O:20])[N:28]=1
Reactant: NS(=O)(=O)c1cccc2c1SCCS2
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(NC(=O)NS(=O)(=O)c2cccc3c2SCCS3)nc(OC)n1
Temperature: 25 °C

Procedure:
To a solution of 2.5 g 1,4-benzodithian-5-sulfonamide, prepared in Example 16, in 50 ml methylene chloride at ambient temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature 2.0 g of methyl[4,6-Dimethoxy-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 3 is added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid, and 10 drops hydrochloric acid are sequentially added. The organic phase is separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from an appropriate organic solvent gives a solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6](C(OC(C)(C)C)=O)[C:7](=O)[NH:8][C:4]=2[CH:3]=1.[C:19](=[O:22])([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:19](=[O:22])[N:8]([CH3:7])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
tert-Butyl 5-bromo-2-oxo-2,3-dihydrobenzo[d]imidazole-1-carboxylate (12 g, 38 mmol) (Puwen Zhang, et. al., Bioorganic & Medicinal Chemistry Letters 11 (2001) 2747-2750 hereby incorporated by reference) and anhydrous disodium carbonate (3.2 mL, 77 mmol) were mixed in 200 mL THF. To this mixture was added dimethyl sulfate (15 mL, 153 mmol). The mixture was stirred at room temperature for 18 hours. The solvent was evaporated. The residue was dissolved in EtOAc and washed with brine and dried over sodium sulfate. The solvent was evaporated. The residue was taken up in MeOH (50 mL) and allowed to stand 18 hours. The solvent was evaporated, and the residue was triturated from MeOH (25 mL) to provide the product as a white solid (8.7 g, 100%). LCMS (API-ES) m/z: 227, 229 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25](S(C)(=O)=O)[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:40]>C1COCC1>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([O:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:40]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: OCC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(OCC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
NaH (15 mg, 0.6 mmol) was added to 2-(hydroxymethyl)-1,3-propanediol in THF (5 mL). The mixture was allowed to stir at 23° under Ar for 10 min and was then cooled to −78°. The product of Example 48 (224 mg, 0.5 mmol) in THF (5 mL) was added at −78° and the mixture allowed to warm to 23° and stir for 2 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 70% EtOAc/CH2Cl2 the title compound as a white-amorphous solid. mp 77-81°, LC MS m/z=472 (MH+) Retention time=1.79 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M95) (0.44 g, 0.92 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (180 mg, 89%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]4[N:29]=[C:28]([CH3:30])[N:27](COCC[Si](C)(C)C)[C:24]4=[N:25][CH:26]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]4[N:29]=[C:28]([CH3:30])[NH:27][C:24]4=[N:25][CH:26]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: Cc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2[nH]1
Yield: 36.2 %

Procedure:
0.70 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline and 825 μl of trifluoroacetic acid in 8 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 120 hours). The cooled reaction solution is diluted with dichloromethane and washed with sodium hydrogencarbonate solution. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-30% in 13 min), giving 0.19 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline (“A4”) as white solid (yield 36%, content 97%); MS-FAB (M+H+)=393.1; Rf (polar method): 1.39 min;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.[CH3:22]C1NC2C(C=1C(Cl)=O)=CC=CC=2>>[CH3:22][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH2:13][C:14]13[CH2:15][CH2:16][N:17]([CH2:20][CH2:21]1)[CH2:18][CH2:19]3)=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: Cc1[nH]c2ccccc2c1C(=O)Cl
Product: Cc1[nH]c2ccccc2c1C(=O)OCC12CCN(CC1)CC2

Procedure:
Quinuclidin-4-ylmethyl 2-methyl-1H-indole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 2-methyl-1H-indole-3-carbonyl chloride as the electrophile.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:29]=[CH:28][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)=O.FC(F)(F)C(O)=O.[CH2:38]([N:45]1[CH2:50][CH2:49][CH2:48][CH:47]([NH:51][NH2:52])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[CH2:38]([N:45]1[CH2:50][CH2:49][CH2:48][CH:47]([N:51]2[C:5]([C:7]3[CH:29]=[CH:28][C:10]4[C:11]5[N:12]([CH:16]=[C:17]([C:19]6[N:23]([CH:24]([CH3:25])[CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=6)[N:18]=5)[CH2:13][CH2:14][O:15][C:9]=4[CH:8]=3)=[CH:4][CH:3]=[N:52]2)[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: NNC1CCCN(Cc2ccccc2)C1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/C=C/N(C)C)cc2OCC3)n(C(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCN(Cc5ccccc5)C4)cc2OCC3)n(C(C)C)n1
Reaction time: 8 h

Procedure:
(E)-3-(dimethylamino)-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)prop-2-en-1-one (0.366 g, 0.000901 mol), 1-benzyl-3-hydrazinylpiperidine trifluoroacetic acid salt (0.376 g, 0.00135 mol), and N,N-Diisopropylethylamine (0.392 mL, 0.00225 mol) was mixed in Ethanol (9 mL, 0.2 mol). The reaction mixture was heated to reflux and was stirred overnight. LCMS showed complete conversion to desired product. The reaction mixture was cooled to room temperature and concentrated to dryness and purified by rHPLC to give 9-(1-(1-benzylpiperidin-3-yl)-1H-pyrazol-5-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[N:13]=[C:14]([C:17](OCC)=[O:18])[S:15][CH:16]=2)[N:7]=1)([O-:5])=[O:4].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[N:13]=[C:14]([CH2:17][OH:18])[S:15][CH:16]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)c1nc(Cn2ncc([N+](=O)[O-])n2)cs1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnn(Cc2csc(CO)n2)n1
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of ethyl 4-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazole-2-carboxylate (845 mg, 2.98 mmol) in THF (30 mL) was treated dropwise at 0° C. with DiBAL-H (11.3 mL of a 1.0 M solution in toluene, 11.3 mmol) and the resulting solution was stirred for 1 h at 0°. Rochelle's salt solution (100 mL) was added and the mixture was stirred for 1 h at rt. The aq. layer was extracted with EA (2×40 mL) and the combined org. layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA)) gave the title compound as a yellow oil. TLC: rf (4:6 hept-EA)=0.25. LC-MS-conditions 07: tR=0.54 min, [M+H]+=241.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=2.C(OCC)(=O)C.[CH3:40][N:41](C=O)C>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>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16]([C:40]#[N:41])[CH:15]=2
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(C#N)ccc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
Trifluoro-methanesulfonic acid 3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester (862 mg, 1.766 mol), Zn (CN)2 (310 mg) and Pd(PPh3)4 (204 mg) were dissolved in DMF (12 mL) at room temperature in a sealed tube. After 10 min, the reaction mixture was heated to 150° C. for 4 h. The reaction mixture was cooled to room temperature and ethyl acetate (200 mL) was added. The reaction mixture was then poured into a separation funnel, washed with water (2×100 ml) and brine (2×100 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 30-50% ethyl acetate in hexanes to yield 3-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile as a slightly yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[S:20][C:19]([CH:21]=[C:22]3[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]3)=[N:18][CH:17]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:7]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[S:20][C:19]([CH2:21][CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]3)=[N:18][CH:17]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)C1CCC(=Cc2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(Cc2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)methylidene]cyclohexanecarboxylate (175 mg, 0.390 mmol) was taken up in ethanol (5 mL), and palladium on carbon (10% loading, 104 mg, 0.098 mmol) was added. The reaction was purged with hydrogen gas (3×) and stirred under a hydrogen atmosphere (via balloon) overnight at room temperature. The mixture was then filtered through CELITE, concentrated under reduced pressure, and the residue purified by flash chromatography on silica gel (0-50% ethyl acetate in hexanes) to provide ethyl 4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate (yellow gum) as a 3:1 mixture of diastereomers. MS ESI calc'd. for C25H31N4O2S [M+H]+ 451. found 451. 1H NMR (500 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.34 (d, J=5.0, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.51 (s, 1H), 7.03 (s, 1H), 6.74 (d, J=5.0 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 2.88 (d, J=7.3 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 1.93-1.83 (m, 4H), 1.62-1.45 (m, 4H), 1.24 (d, J=9.5 Hz, 2H), 1.18-1.14 (m, 3H). rhSyk activity=++
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17](CC3C=CC=CC=3)[CH:16]=[C:15]([OH:26])[C:8]=2[S:9][C:10]=1[NH:11]C(=O)C)=[O:5])[CH3:2].OS(O)(=O)=O>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][C:16]([CH2:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:8]=3)=[C:15]([OH:26])[C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c(O)cc(Cc3ccccc3)cc12
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)c1c(N)sc2c(O)c(Cc3ccccc3)ccc12
Reaction time: 192 h

Procedure:
Compound 02-6 (4.3 g, 11.7 mmol) was dissolved in MeOH (350 mL), conc. H2SO4 (2 mL) was added and the mixture was stirred for 8 days. The mixture was concentrated to half of the original volume. H2O was added and the pH was cautiously adjusted to 8 with conc. NH4OH. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the crude product, which was purified by column chromatography (SiO2, EtOAc/hept=1/4+1% Et3N to 1/1). The product was obtained in only 80% purity according to HPLC and therefore subjected to automated column chromatography to give a-2 (2.1 g, 6.4 mmol, 55%) as a brown-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([C:27](=[O:29])[CH3:28])=[CH:35][CH:34]=2)(=[O:38])=[O:37])[CH2:24][CH3:25])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(C(C)=O)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-acetylbenzenesulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]12[CH2:29][CH:17]3[CH2:18][C:19]([NH:21]C(=O)OC(C)(C)C)([CH2:20]1)[CH:15]([CH2:16]3)[CH2:14]2.FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:19]12[CH2:18][CH:17]3[CH2:29][C:13]([CH2:12][N:3]4[C:2](=[O:1])[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:4]4=[O:11])([CH2:14][CH:15]1[CH2:16]3)[CH2:20]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.5 %

Procedure:
To a stirred solution of the compound obtained from step I (0.45 g, 1.12 mmol) in dichloromethane (1.1 mL) at 0° C. was added trifluoroacetic acid (1.1 mL). The reaction mixture was gradually warmed to room temperature and stirred for 1 h. The volatiles were removed under vacuum and the residue was triturated several times with diethyl ether to obtain 2-[(3-aminotricyclo[3.3.1.03,7]non-1-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.4 g) as its trifluoroacetic acid salt in 86% yield. m/z (M+1) 297; 1H NMR (DMSO-d6) 300 MHz δ 8.05 (s (br), 2H), 7.92-7.80 (m, 4H), 3.51 (s, 2H), 2.38-2.30 (m, 1H), 2.30-2.22 (m, 1H), 1.85-1.66 (m, 6H), 1.60-1.50 (m, 3H), 1.45-1.38 (m, 1H).
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][O:56][C:57]1[CH:69]=[CH:68][C:60]([CH2:61][C:62]2N=C(N)[S:64][N:63]=2)=[CH:59][CH:58]=1>ClCCl>[CH3:55][O:56][C:57]1[CH:69]=[CH:68][C:60]([CH2:61][C:62]2[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])[S:64][N:63]=2)=[CH:59][CH:58]=1
Reactant: COc1ccc(Cc2nsc(N)n2)cc1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(Cc2nsc(NC(=O)[C@H](CC(C)C)N3CC(Oc4ccccc4Cl)=CC3=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 60 mg, 0.19 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol). The resulting solution was stirred for 5 min before 3-(4-methoxy-benzyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.23 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(4-methoxy-benzyl)-[1,2,4]thiadiazol-5-yl]-amide (48 mg, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C26H27ClN4O4S [M+H]+ 527.1515, observed 527.1514; 1H NMR MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.44 (br. s., 1H), 1.54-1.71 (m, 1H), 1.71-1.90 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 4.25 (d, J=18.4 Hz, 1H), 4.48 (d, J=18.4 Hz, 1H), 4.79 (s, 1H), 4.97 (dd, J=10.9, 4.8 Hz, 1H), 7.33 (td, J=7.8, 1.5 Hz, 1H), 7.43 (td, J=7.8, 1.4 Hz, 1H), 7.50 (dd, J=7.8, 1.5 Hz, 1H), 7.62 (dd, J=7.8, 1.4 Hz, 1H), 13.24 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O1CCOCC1>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C=Nc1cccc(I)c1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(I)c1)N1CCOCC1

Procedure:
A solution of 3-iodophenylisocyanate (0.1 g, 0.41 mmol) and morpholine (0.04 mL, 0.45 mmol) in 2 mL dioxane were heated at 100° C. overnight. The solvent was evaporated and the resulting product was used without purification.