Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNC1CCC1.[CH:46]1([N:50]2[CH2:55][CH2:54][C@H:53]([CH3:56])[N:52]3[C:57](=[O:85])[C:58]4[N:59]([CH:61]=[C:62]([C:74]([NH:76][CH2:77][C:78]5[CH:83]=[CH:82][C:81]([F:84])=[CH:80][CH:79]=5)=[O:75])[C:63](=[O:73])[C:64]=4[O:65]CC4C=CC=CC=4)[CH2:60][C@@H:51]23)[CH2:49][CH2:48][CH2:47]1>>[CH:46]1([N:50]2[CH2:55][CH2:54][C@H:53]([CH3:56])[N:52]3[C:57](=[O:85])[C:58]4[N:59]([CH:61]=[C:62]([C:74]([NH:76][CH2:77][C:78]5[CH:83]=[CH:82][C:81]([F:84])=[CH:80][CH:79]=5)=[O:75])[C:63](=[O:73])[C:64]=4[OH:65])[CH2:60][C@@H:51]23)[CH2:47][CH2:48][CH2:49]1
Reactant: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: C[C@H](N)CCNC1CCC1
Agent: Cl
Product: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(O)c3C(=O)N12

Procedure:
In a similar manner to that described in example Z-35a, from 16 (18 mg, 0.39 mmol) and [(3S)-3-Aminobutyl]cyclobutylamine bis hydrochloride (23 mg, 0.107 mmol), (4S,12aS) 1-cyclobutyl-N-[(4-fluorophenyl)methyl]4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a white solid after purification by HPLC (4.5 mg, 25% 2 steps), 1H NMR (CDCl3) δ 12.54 (s, 1H), 10.48 (s, 1H), 8.20 (s, 1H), 7.31 (m, 2H), 6.98 (m, 2H), 5.02 (m, 1H), 4.61-4.57 (m, 2H), 4.26-4.14 (m, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.49 (m, 1H), 2.12 (m, 1H), 2.05-1.87 (m, 3H), 1.84-1.61 (m, 3H), 1.46 (m, 1H), 1.32 (m, 3H); ES+ MS: 455 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:12][C:13](=[N:17][OH:18])[C:14](=O)[CH3:15].Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]([CH3:15])=[C:13]([CH3:12])[N+:17]=2[O-:18])[CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10]
Reactant: CC(=O)C(C)=NO
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: O=CO
Product: Cc1oc(-c2cc(Cl)c(O)c(Cl)c2)[n+]([O-])c1C

Procedure:
2-(3,5-Dichloro-4-hydroxyphenyl)-4,5 -dimethyloxazole N-oxide was prepared from 19.1 g 3,5-dichloro-4-hydroxybenzaldehyde and 10.1 g butanedione mono-oxime in formic acid in the presence of hydrogen chloride gas. There was obtained 12.2 g of product, m.p. 221°-223° C.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[N:9]=[N:8][C:7]([N:10]([CH3:12])[CH3:11])=[N:6][CH:5]=1>C(O)(=O)C>[Br:3][C:4]1[C:5](=[O:1])[NH:6][C:7]([N:10]([CH3:12])[CH3:11])=[N:8][N:9]=1
Reactant: CN(C)c1ncc(Br)nn1
Reactant: OO
Solvent: CC(=O)O
Product: CN(C)c1nnc(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
Hydrogen peroxide (27% strength solution in water, 0.53 ml, 4.56 mmol) was added at 5° C. to a solution of 6-bromo-3-dimethylamino-1,2,4-triazine (IX) (J. Org. Chem. 43 (1978) 2514) (500 mg, 2.46 mmol) in glacial acetic acid (4 ml), and the reaction mixture was stirred at 25° C. for 12 hours. The resulting precipitate was collected, washed with water, dried in the air and recrystallized from ethanol. The ketone (X) (368 mg, 68%) was obtained as white crystals of melting point 261-262° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1Br)([CH3:8])[CH3:7].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27]>C1(C)C=CC=CC=1.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](=[O:25])[CH:4]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:26]=[CH2:27])([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)(C)c1cc(F)ccc1Br)C(=O)c1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(F)cc1C(C)(C)CC(C(=O)OC)C(=O)c1ccccc1

Procedure:
A solution of 0.53 g (1.25 mmol) of 2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl ester and 77 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium in 40 ml of toluene is refluxed with vinyl(tributyl)stannane for 8 hours. Then, it is concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 320 mg of product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:24][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.8 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of acetone, and 8.3 g of anhydrous potassium carbonate and 14.2 g of methyl iodide are added thereto. The mixture is stirred at room temperature for 6 days. The reaction mixture is treated in the same manner as described in Preparation 1-(2), whereby 9.0 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 89.8% The physico-chemical properties of this product are identical with those of the sample obtained in Preparation 1-(2).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]([CH3:17])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1nc(C)c(C(=O)NCc2ccccc2)s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(N(C)C(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of crude N-benzyl-4-methyl-2-(methylamino)thiazole-5-carboxamide (0.040 g, 0.15 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (64 μL, 0.45 mmol) in dichloromethane (5 mL) was added benzoyl chloride (19 μL, 0.17 mmol) at 0° C. and the reaction mixture was allowed to warm to ambient temperature over 18 h. The reaction was quenched by the addition of saturated soldium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (30/70 to 50/50) to afford the title compound (0.040 g, 0.11 mmol); 1H NMR (CDCl3, 400 MHz) δ 7.47-7.35 (m, 5H), 7.30-7.17 (m, 5H), 6.05 (s, 1H), 4.51 (s, J=5.6 Hz, 2H), 3.55 (s, 3H), 2.60 (s, 3H); MS (ES+) m/z 366 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CC(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[CH:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:11][N:10]([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(Cl)cc2)c(=O)c(-c2cccc(Cl)c2)c1
Agent: O=c1cccc[nH]1
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Product: CN1CC(c2ccc(Cl)cc2)C(=O)C(c2cccc(Cl)c2)C1

Procedure:
A 10 g. portion of 3-(3-chlorophenyl)-5-(4-chlorophenyl)-1-methyl-4(1H)-pyridinone was made from 33.6 g. of the corresponding 2-propanone by the procedures of Examples 1-3. The pyridinone was reduced with lithium aluminum hydride and the reaction mixture was separated by chromatography as described in the examples above. The products of Examples 15 and 16 were obtained as a mixture containing both, combined yield 2.1 g., m.p. 125.5°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Li+].[OH-].Cl>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of methyl 3-amino-6-(2-fluoro-5-isopropylcabamoyl)phenyl)picolinate (1.0 equiv) in THF (0.5 M), was added 1M LiOH (4.0 equiv). After stirring for 4 hours at 60° C., 1 N HCl (4.0 equiv.) was added and the THF was removed in vacuo. The resulting solid was filtered and rinsed with cold H2O (3×20 mL) to yield 3-amino-6-(2-fluoro-5-isopropylcabamoyl)phenyl)picolinic acid (98%). LCMS (m/z): 318.1 (MH+); LC Rt=2.4 min.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc(CNc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)cc1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 4-methoxy-benzylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.89 (t, 1H), 7.63 (d, 1H), 7.25 (d, 2H), 7.0-6.93 (2H), 6.90 (d, 2H), 6.16 (s, 1H), 4.45 (d, 2H), 3.92 (t, 2H), 3.82 (s, 3H), 3.73 (s, 3H) and 2.92 (t, 2H); MS (ESI) (M+H)+ 364.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(N(C(C)C)CC)(C)C.Cl[C:19]1[N:24]([CH3:25])[C:23](=[O:26])[C:22]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:21]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([Cl:40])[CH:35]=2)[N:20]=1>ClCCl>[Cl:40][C:36]1[CH:35]=[C:34]([C:21]2[N:20]=[C:19]([N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH2:3][O:2][CH3:1])[N:24]([CH3:25])[C:23](=[O:26])[C:22]=2[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[CH:39]=[CH:38][N:37]=1
Reactant: Cc1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n(C)c2=O)c1
Reactant: COC[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC1CCCN1c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (S)-2-methoxymethyl-pyrrolidine (0.172 g, 1.5 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.35 mL diisopropylethylamine (2.0 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-6-(2-chloropyridin-4-yl)-3-methyl-5-m-tolyl-3H-pyrimidin-4-one (0.345 g, 1.0 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.40 g as pale yellow solid. MS (ES+): 425 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](C=CC3C=CC=CC=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.CO.O=[O+][O-].[CH:32]([O:37][CH3:38])([O:35][CH3:36])OC>C(Cl)Cl>[CH3:38][O:37][CH:32]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1)[O:35][CH3:36]
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: COC(OC)OC
Agent: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1nn(COCC[Si](C)(C)C)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole [Example 14, step (i)] (1.28 g, 2.69 mmol) in CH2Cl2 (40mL)/MeOH (40 mL) was stirred at −78° C. The reaction was treated with ozone until a blue color persisted, and then was purged with argon. Methyl sulfide (4 mL) was added, and the reaction stirred 4 h while warming to r.t. Concentration in vacuo gave a crude mixture of acetal and aldehyde, which was converted completely to the acetal by stirring in trimethyl orthoformate (10 mL) with Amberlyst 15(wet) acidic ion-exchange resin (0.8 g) for 1 h. The resin was removed by filtration, and the solution was concentrated in vacuo. Purification by silica gel chromatography gave 1.11 g (92%) of 3-(1,1-dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.48 (dd, 1H, J=8.4, 1.2 Hz), 5.77 (s, 1H), 5.69 (s, 2H), 3.53 (t, 2H, J=8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J=8.4 Hz), −0.06 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([CH2:21][C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](O)=[O:19])[CH:14]=[CH:15][CH:16]=1.ClCCCl.O.O[N:44]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>ClCCl>[Cl:2][C:3]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([CH2:21][C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([NH2:44])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](CN(CCCOc1cccc(CC(=O)O)c1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@H](CN(CCCOc1cccc(CC(N)=O)c1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution (S)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)acetic acid hydrochloride salt (50 mg, 0.1 mmol) in dichloromethane, 1,2-dichloroethane (EDC, 19.2 mg, 0.1 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 13.6 mg, 0.1 mmol), triethylamine (Et3N, 14 μl, 0.1 mmol) and ammonia (1.0M in dioxane, 0.24 ml) were added. After the resulting mixture was stirred at room temperature for over night it was washed with 0.1N HCl, saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified with HPLC to give the tittle compound as a light yellow oil 30 mg, yield 60%. MS m/e 519.0 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[N:29]=1.C(N(CC)CC)C>C(#N)C>[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][N:40]([CH2:6][CH2:7][O:8][C:9]4[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=4)[CH:15]=[O:16])[CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[N:29]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CS(=O)(=O)OCCOc1cccc(C=O)c1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(C=O)c4)CC3)C2)cs1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2-(3-Formylphenoxy)ethyl methanesulfonate (example 10, step a) (0.38 g) was added to a solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.62 g) and triethylamine (0.55 mL) in acetonitrile (5 mL) and the resulting mixture stirred for 16 h at 65° C. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was separated and extracted with ethyl acetate (2×25 mL). The organic phases were combined, washed with brine (25 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 47.5:47:5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient to give the subtitled compound as a yellow oil. Yield 0.48 g.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=3)[N:12]=2)=[CH:8][C:7]([CH3:29])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:24][CH:23]=3)[N:12]=2)=[CH:8][C:7]([CH3:29])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: Cc1cc(Nc2nn(-c3ccc(Cl)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Product: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
4-(2-tert-Butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-chlorophenyl)-2H-phthalazin-1-one (0.10 g, 0.25 mmol), piperidine (0.025 g, 0.29 mmol), NaOtBu (0.033 g, 0.34 mmol), tris-(dibenzylideneacetone)-dipalladium (0.06 g, 0.008 mmol) and 2-(di-t-butylphosphino)-biphenyl (0.004 g, 0.014 mmol) under argon were heated to 100° C. for 19 hours, and then allowed to cool to RT. The solvent was evaporated in vacuum, the residue was diluted in H2O (30 ml) and the resulting solid was collected by filtration. Purification of the raw product by preparative HPLC gave the title compound (0.014 g, 13% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.35 (1H, d), superimposed by 8.34 (1H, s), 8.29 (1H, d), 8.01 (1H, t), 7.92 (1H, t), 7.31 (2H, d), 6.92 (2H, d), 5.94 (1H, s), 3.16 (4H, m), 1.61 (4H, m), 1.55 (9H, s), superimposes 1.54 (2H, m); MS (ESI+)=457.16 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:25]2=[S:26])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1NCCCNCC(C)C
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1CCCN(CC(C)C)C1=S
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
To an ice-cold solution of the diamine of Step A (5.0 g) and triethylamine (5.2 mL) in dry chloroform (50 mL) under nitrogen was added thiophosgene (1.5 mL). After 5 minutes at ambient temperature, additional thiophosgene (1.0 mL) was added. After 10 minutes the reaction was quenched with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a pale brown solid which was triturated with diethyl ether to give the title product (2.8 g, 48.1%) as a white solid, m.p. 96-98° C.
Reaction SMILES: [C:1]1([CH2:6][NH2:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:16][Si:17]([CH3:25])([CH3:24])[O:18][Si:19]([CH2:22]Cl)([CH3:21])[CH3:20].C1(C)C=CC=CC=1>O>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[CH2:6][N:7]1[CH2:20][Si:19]([CH3:22])([CH3:21])[O:18][Si:17]([CH3:25])([CH3:24])[CH2:16]1
Reactant: C[Si](C)(CCl)O[Si](C)(C)CCl
Reactant: NCc1cccs1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si]1(C)CN(Cc2cccs2)C[Si](C)(C)O1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To a solution containing 22.6 g. (0.2 mole) of 2-thenylamine, 44.4 g. (0.44 mole) of triethylamine and 50.0 g. of acetonitrile dried over molecular sieves there is added 46.2 g. (0.2 mole) of 1,3-bis-chloromethyl-1,1,3,3-tetramethyl-disiloxane. The resulting homogenized solution is allowed to stand for 3 days and then heated in a bath at 90° C. for 36 hours. After cooling the mixture is then equiliberated between toluene and water, the organic phase is then washed with two more portions of water and concentrated to give 61.5 g. of a crude oil. Vacuum distillation through a Vigreux column gives 4-(2-thienylmethyl)-2,2,6,6-tetra-methyl-1-oxa-4-aza-2,6-disilacyclohexane; b.p. 78° to 80° C. at 0.1 to 0.11 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].S(Cl)(O[CH2:26][Cl:27])(=O)=O>ClCCl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:26][Cl:27])=[O:15])[CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 g, 13.1 mmol) in dichloromethane (40 mL) and water (50 mL) was added NaHCO3 (4.4 g, 52.3 mmol) and tetrabutylammonium hydrogen sulfate (444 mg, 1.3 mmol). After stirring the mixture in an ice bath at 0° C. for ˜10 min, chloromethyl chlorosulfate (2.59 g, 15.7 mmol) in 10 mL of dichloromethane was added dropwise. The reaction mixture was allowed to warm up to rt and stirred vigorously overnight. The mixture was transferred to a separatory funnel with dichloromethane and water (200 mL, each). The organic layer was washed with additional water and brine, dried (Na2SO4), and concentrated in vacuo to give 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate as a clear oil (3.5 g, 96% yield). This material was used without further purification. 1H NMR (DMSO-d6) δ 1.26-1.48 (m, 11H, CHH, CHH, tertBu), 1.83 (dd, J=3.0, 13.2 Hz, 2H, CHH, CHH), 2.58-2.75 (m, 1H, CH), 2.74-2.99 (m, 2H, CHH, CHH), 3.61-4.02 (m, 2H, CHH, CHH), 5.87 (s, 2H, CH2O); 13C NMR (DMSO-d6) δ 27.16, 27.98, 39.58, 42.35, 69.41, 78.67, 153.75, 172.25; LCMS: MH=278.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=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>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 70 °C

Procedure:
A 250 ml RB flask was charged with (R)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (4.06 g, 8.88 mmol), pyridin-3-ylboronic acid (1.419 g, 11.55 mmol), tetrakis(triphenylphosphine)palladium(0) (1.026 g, 0.888 mmol). DME (63.4 mL) and sodium carbonate (13.32 mL, 26.6 mmol) (2M solution) were added and the mixture was heated at 70° C. for 15 hrs. The mixture was diluted with water and ethyl acetate, filtered and organic layer was separated and concentrated. The crude material was purified by silica gel chromatography (0-50% gradient of 90/10/1 DCM/MeOH/NH4OH in DCM) to give (S)-2′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.