Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[C:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[CH:70]=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[C:68](Br)=[CH:67][C:66]=3[F:77])=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[C:66]([F:77])=[CH:67][C:68]([C:30]4[CH:31]=[CH:32][C:27]([C:25]5[N:26]=[C:22]([C@@H:18]6[CH2:19][CH2:20][CH2:21][N:17]6[C:15](=[O:16])[C@@H:11]([NH:10][C:9]([O:8][CH3:7])=[O:42])[CH:12]([CH3:14])[CH3:13])[NH:23][CH:24]=5)=[CH:28][CH:29]=4)=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[CH:70]=3)=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (470 mg, 3.4 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (340 mg, 0.68 mmol) and (2S,5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.68 mmol; Preparation 49) dissolved in toluene (2.5 mL) and water (0.73 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce (2S,5R)-4-[5-(5-fluoro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a red solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH2:9]Cl)[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>CN(C)C=O>[C:17]([O:20][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][O:20][C:17](=[O:19])[CH3:18])[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(C(C)C)c(CCl)cc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(COC(C)=O)c(C(C)C)cc1C(C)C

Procedure:
40.0 g (154 mmol) of the compound from Example 1 and 22.7 g (277 mmol) of sodium acetate are heated overnight at 80° C. in 200 ml of dimethylformamide. After distilling off the solvent, the residue is taken up with petroleum ether, washed with water and dried using sodium sulphate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:34]4[CH:35]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:33]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: CN1CCN(Cc2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(Cc2cccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-benzyl)-4-methyl-piperazine (77.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.043, 35%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, J=8.6 Hz, 2H), 8.13 (d, J=8.6 Hz, 2H), 7.59-7.51 (m, 3H), 7.45-7.43 (m, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.06 (dd, J=5.1, 3.3 Hz, 1H), 6.98-6.94 (m, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.70-2.32 (m, 8H), 2.28 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50](OC)=[O:51])=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([NH:2][CH3:1])=[O:51])=[N:46]2)=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Agent: CN
Product: CNC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and methylamine. 1H-NMR (400 MHz, CDCl3, δ) 8.42 (d, J=6.8 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.85 (s, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.50 (broad, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.29 (m, 1H), 6.87 (m, 1H), 6.34 (s, 2H), 3.08 (d, J=5.1 Hz, 3H) ppm; m/e 367, 369.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[Si:13]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 1400 g (8.1 mol) of 3-bromophenol, 1218 g (8.1 mol) of tert-butylchlorodimethylsilane and 1376 g (20.2 mol) of imidazole in 1600 mL of N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into pH 8 aqueous buffer solution and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give 2314 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as an orange oil. NMR (CDCl3, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[C:26]([O:29][CH2:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:22]1)=[O:32])(=[O:28])[CH3:27]
Reactant: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5 g of the crude product from Example 20A are suspended in 24 ml of dichloromethane and cooled to 0° C. 1.88 g (13.79 mmol) of acetoxyacetyl chloride and 5.9 ml (42.42 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 8 h. After addition of 25 ml of dichloromethane the mixture is washed once with 10 ml of water and once with 10 ml of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 20:1→1:1).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.CCOCC>COCCOCCOC>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:2]3[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1cccc2[nH]ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]ccc12

Procedure:
Methyl 2,4-difluorobenzoate (1.53 g), K3PO4 (1.89 g) and 4-hydroxyindole (1.08 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M aqueous NaOH solution, and brine, and dried over Na_SO4. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:30].COC1CCCC1>C1COCC1>[ClH:30].[CH:26]1([CH2:25][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2cn[nH]c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: COC1CCCC1
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1cn[nH]c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl(cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (72 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0° C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (4.5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (45 mg).
Reaction SMILES: [CH3:1][C:2]([C:4](Cl)=[O:5])=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH3:1][CH:2]1[C:4](=[O:5])[C:13]2=[CH:14][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[CH:11]=[C:12]2[CH2:3]1
Reactant: c1ccc2c(c1)CCCC2
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1=O)CCCC3
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Methacryl chloride (37.5 ml, 375 mmol) was added at −70° C. to well-stirred suspension of AlCl3 (100 g, 750 mmol) in CH2Cl2 (600 ml). After 20 min tetrahydronaphthalene (49.5 g, 375 mmol) was added. Reaction mixture was allowed to warm to room temperature, stirred for 16 h and poured into ice water-HCl (1 l/150 ml). Organic layer was separated, water layer was extracted by CH2Cl2 (2100 ml). Combined organic phases were washed by water, aq. NaHCO3, dried over MgSO4 and evaporated. Vacuum distillation (130-140° C./0.5 Torr) a mixture of ketones. After storage within 5 days desired isomer stays liquid and can be separated by decantation. The yield 30 g (40%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH2:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH:59]2[C:64]2[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=2)=[N:54][CH:55]=1.Cl>CN(C=O)C>[Cl:70][C:67]1[CH:68]=[CH:69][C:64]([CH:59]2[CH:58]([CH2:57][O:56][C:53]3[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][N:54]=3)[CH2:63][CH2:62][N:61]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:15][CH:14]=3)=[O:13])[CH2:60]2)=[CH:65][CH:66]=1
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Reactant: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc(C(=O)N3CCC(COc4ccc(Cl)cn4)C(c4ccc(Cl)cc4)C3)cc2)n1

Procedure:
A mixture of 18 mg (0.08 mmol) 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid, 43 mg (0.11 mmol) HATU, 0.1 mL DIPEA and 32 mg (0.09 mmol) 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride in 2 mL DMF was reacted at room temperature over night. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 32 mg (64%) of the title compound as white foam. MS (m/e): 523.3 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:23][CH2:22][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.O.Cl.[H][H]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:23][CH2:22][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2N2CCN(CCc3ccccn3)CC12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2N2CCN(CCC3CCCCN3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-3-[2-(2-pyridinyl)-ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and 60 ml. ethanol containing 14 ml. conc. hydrochloric acid, was shaken with 1.2 g. of PtO2 under 45 psi. hydrogen pressure. Solution was filtered, concentrated under vacuum, and residue crystallized once from ethanol and then from methanol. After filtration and drying the dihydrochloride salt of the title compound had a m.p. of 268°-271° C. (dec.); yield: 3.5 g.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:17][CH2:16]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].I[C:30]1[CH:42]=[CH:41][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=1.CNC1CCCCC1NC>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:30]3[CH:31]=[CH:32][C:33]([CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:41][CH:42]=3)[CH:13]=[C:12]([CH:15]3[CH2:16][CH2:17][CH:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:19][CH2:20]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2[nH]cc(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2n1
Reactant: Ic1ccc(CN2CCOCC2)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCNc1ncc2c(n1)c(C1CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(CN2CCOCC2)cc1
Temperature: 195 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of N-butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (59 mg, 0.14653 mmol) and 4-iodobenzyl morpholine (67 mg, 0.22 mmol) in NMP (1 mL) was added CuI (3 mg, 0.022 mmol) and N,N′-dimethylcyclohexane-1,2-diamine (2 mg, 0.044 mmol). The reaction mixture was stirred under microwave irradiation at 195° C. for 30 min. Then the reaction was diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (85 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.17 (s, 1H), 4.86 (s, 1H), 3.71-3.52 (m, 4H), 3.44-3.38 (m, 4H), 3.32-3.17 (m, 1H), 2.81-2.71 (m, 2H), 2.45-2.33 (m, 4H), 2.15-2.04 (m, 2H), 1.96-1.83 (m, 2H), 1.61-1.29 (m, 8H), 0.94-0.75 (m, 12H), 0.00 (s, 6H). MS m/z 578.4 [M+H]+.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>>[OH:14][C@H:13]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COP([O-])OC
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Product: COc1ccc([C@H](O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
The solution of ALB-CN in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 5 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 59 hours, 1N hydrochloric acid was added to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (R)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a yield of 25%. The chemical reaction in this Example is shown in chemical formula 46. ##STR40##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)=[O:10].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:36][CH2:37][CH2:38]I)[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH2:16][N:15]([CH2:38][CH2:37][CH2:36][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:14][CH:13]2[CH2:12]1)=[O:10]
Reactant: O=S(=O)(c1ccccc1)N(CCCI)c1ccc(F)cc1
Reactant: Cc1cccc(C)c1C(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cccc(C)c1C(=O)N1CC2CN(CCCN(c3ccc(F)cc3)S(=O)(=O)c3ccccc3)CC2C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 66 (0.012 g, 0.05 mmol) in MeCN (1 mL) at RT were added N-(4-fluoro-phenyl)-N-(3-iodo-propyl)-benzenesulfonamide (102, 0.025 g, 0.06 mmol) and K2CO3 (0.01 g, 0.075 mmol). The reaction mixture was shaken at 80° C. for 48 h. After cooling to RT, the mixture was diluted with DCM (5 mL), filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC to afford II-2: MS (ES+) m/z=536 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Li])CCC.IC.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][CH3:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: C#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CI
Product: CC#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
Under argon condition, tert-butyl((4-ethynylbenzyl)oxy)dimethyl-silane (247 mg, 1.00 mmol) was dissolved in 5 mL of dry THF, cooled to −78° C., and n-butyl lithium (805 μL, 2.49 M solution in n-hexane, 2.00 mmol) was slowly added thereto. After stirring for 20 minutes at −78° C., iodomethane (313 μL, 5.00 mmol) was added again thereto. Thereafter, the temperature was raised to room temperature and the reaction mixture was stirred for 30 minutes at room temperature. Upon completion of the reaction, the reaction was terminated by adding 10 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (5 mL×4) and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out, and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 253 mg (0.971 mmol, 97%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CN(c2cccc(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of alcohol 103 (6.33 g, 30.0 mmol) in CH2Cl2 (60 mL) was treated with TEA (6.07 g, 8.36 mL, 60 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before MsCl (3.78 g, 2.55 mL, 33.0 mmol, 1.1 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (40 mL) and CH2Cl2 (40 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with H2O (2×40 mL) and saturated aqueous NaCl (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (SR)-methanesulfonic acid 3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 109 (7.69 g, 88.7% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H12FNO5S, LCMS (EI) m/e 290 (M++H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCCC2)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (66%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)cc(Cl)n1

Procedure:
4-Amino-2,6-dichloropyrimidine (0.5 g.) was added to 30 ml. of a 1% solution of sodium methoxide in methanol. The resultant solution was heated at the reflux temperature for 2 hrs. The methanol was then removed by evaporaion and water was added to the residual oil. The precipitate that formed was filtered off, washed with water and dried at 100° C. at a pressure of 100 mm for 18 hrs. There was thus obtained 4-amino-6-chloro-2-methoxypyrimidine having a melting point at 124° C.