Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:1]1([CH:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][C@@H:20]2[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccccc1)N1CCCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCCC1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
A mixture of 2-(azepan-1-yl)-2-phenylacetic acid (476 mg, 2.04 mmol), (R)-quinuclidin-3-ol (311 mg, 2.45 mmol), HOBT (375 mg, 2.45 mmol) and DCC (505 mg, 2.45 mmol) in THF (20 ml) was stirred at room temperature over a week-end. THF was evaporated, the crude was taken up with EtOAc and washed twice with 2M K2CO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography (DCM/MeOH=95/5) to get (R)-quinuclidin-3-yl 2-(azepan-1-yl)-2-phenylacetate (110 mg, 15.7% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:13]=2)[O:9][N:8]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][C:10]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2noc(-c3cc(-c4ccccn4)no3)n2)cc1
Solvent: CC#N
Product: Cc1ccc(-c2noc(-c3onc(-c4ccccn4)c3Br)n2)cc1
Yield: 393.3 %

Procedure:
A solution of 5-(3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (655 mg, 2.15 mmol), N-bromosuccinimide (536 mg, 3.01 mmol), and PdOAc2 (97 mg, 0.430 mmol) in acetonitrile (12 mL) was heated to 120° C. via microwave for 30 minutes. The reaction was repeated three additional times on a similar scale, and the contents of each reaction tube were combined and filtered. The solid was collected, triturated with methanol (10 mL), and collected by vacuum filtration to give 5-(4-bromo-3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (3.24 g, 87% yield). The compound had an HPLC retention time=3.96 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=385+. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3H), 7.35 (d, J=8.03 Hz, 2H), 7.49 (ddd, J=7.65, 4.89, 1.00 Hz, 1H), 7.91 (td, J=7.78, 1.76 Hz, 1H), 8.03 (d, J=7.78 Hz, 1H), 8.12 (d, J=8.28 Hz, 2H), and 8.86 (d, J=4.77 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: C#CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: C#CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a white solid (59 mg, 34%). m.p.=165-167° C.; LCMS (m/e) 505 M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.91 (s, 1H), 8.69 (d, 1H, J=8.9 Hz), 8.11 (s, 1H), 7.55 (d, 1H, J=7.5 Hz), 7.50-7.43 (m, 1H), 7.35 (s, 1H), 7.28-7.22 (m, 1H), 7.16-7.08 (m, 1H), 7.04 (d, 1H, J=8.8 Hz), 6.87 (s, 1H), 6.32 (bs, 1H), 4.32-4.26 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.80-2.69 (m, 6H), 2.35-2.31 (m, 1H).
Reaction SMILES: CO[C:3]([C@@:5]12[C:11]([CH3:13])([CH3:12])[C@@H:8]([CH2:9][CH2:10]1)[CH:7]=[C:6]2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:16][C:15]=1[O:31][CH3:32])=O.COC1C=C(C(C)(CCCCC)C)C=C(OC)C=1B1OC(C)(C)C(C)(C)O1>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>[CH3:32][O:31][C:15]1[CH:16]=[C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:6]1[C@@:5]2([CH3:3])[C:11]([CH3:13])([CH3:12])[C@@H:8]([CH:7]=1)[CH2:9][CH2:10]2
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCC(C)(C)c1cc(OC)c(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@H]3CC[C@]2(C)C3(C)C)c(OC)c1

Procedure:
The title compound was prepared by the general procedure described for compound 11a, using pinacol arylboronate 3 (mixed with 1) 0.755 g, camphor enol triflate 10a 0.5 g (1.76 mmol), Pd(PPh3)4 0.122 g (0.011 mmol) and t-BuNF 2.64 ml (2.64 mmol, 1M solution in THF) to give yellowish oil 0.525 g (75%), which solidified upon standing at −20° C. to give a white solid. mp 34-36° C.; 1H NMR (300 MHz, CDCl3) δ ppm 6.50 (s, 2H), 5.87 (d, J=3.27 Hz, 1H), 3.74 (s, 6H), 2.37 (t, J=3.46, 1H), 1.88 (m, 1H), 1.65 (m, 1H), 1.61 (m, 2H), 1.55 (m, 1H), 1.30 (s, 6H), 1.15 (m, 1H), 1.19-1.26 (m, 6H), 1.07-1.18 (m, 2H), 1.05 (s, 3H), 0.86 (t, J=6.71 Hz, 3H), 0.83 (s, 3H), 0.82 (s, 3H). Exact mass calculated for C27H42O2 m/e 398.32. found 398.79. Anal. calcd. for C27H42O2: C, 81.35; H, 10.62. Found: C, 81.08; H, 10.69.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([C:29]1[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=1)=[O:28])[CH2:22][CH2:21]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([C:29]1[N:30]=[CH:31][N:32]=[C:33]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:34]=1)=[O:28])[CH2:22][CH2:21]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(Cl)ccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
80 mg (0.27 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (dihydrochloride) were added to 100 mg (0.34 mmol) (5-chloro-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 22 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered. The purification was carried out using a silica gel column. The product fractions were combined and the solvent was eliminated using the rotary evaporator. The residue was stirred with water, suction filtered and dried.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][NH:4][CH2:3]1.CS[C:11]1[N:12]=[N:13][CH:14]=[CH:15][N:16]=1.N1(C2N=NC=CN=2)CCNCC1>>[CH3:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][N:16]=2)[CH2:3]1
Reactant: CC1CNCCC1O
Reactant: CSc1nccnn1
Agent: c1cnc(N2CCNCC2)nn1
Product: CC1CN(c2nccnn2)CCC1O

Procedure:
Intermediate 5c is synthesised from 3-methyl-piperidin-4-ol and the precursor 2a according to the procedure described for the synthesis of 5a. Intermediate 5c is isolated in solid form with a 47% yield.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([NH2:6])=[NH:5].[F:7][CH:8]([C:13](OC)=[O:14])[C:9](OC)=[O:10].C[O-].[Na+]>CO>[F:7][C:8]1[C:9](=[O:10])[N:5]=[C:4]([CH2:3][F:2])[NH:6][C:13]=1[OH:14]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: N=C(N)CF
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1nc(CF)[nH]c(O)c1F
Temperature: 50 °C

Procedure:
2-Fluoro-acetamidine hydrochloride salt (11.2 g, 100 mmol) and dimethyl fluoromalonate (15 g, 100 mmol) in anhydrous methanol (300 mL) were treated with solid NaOMe (16.2 g, 300 mmol) and heated to 50° C. with stirring. When LCMS showed formation of the desired product, the solvent was evaporated to dryness, and the residue was neutralized with concentrated HCl (20 mL). The white precipitate was collected by filtration to give 5-fluoro-2-(fluoromethyl)-6-hydroxy-4(1H)-pyrimidinone (100% yield). LCMS: (M+H)+: 163.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18](Br)=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][O:26]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.[Cl-].[NH4+]>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([N:29]3[C@H:28]([CH2:30][O:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:27][O:26][C:25]3=[O:24])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)c(F)c2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)c(F)c2)CC1
Yield: 31.2 %

Procedure:
To a mixture of 4-(4-bromo-3-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (3.49 g) described in Preparation Example 90, benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.99 g), potassium carbonate (2.49 g) and copper (I) iodide (343 mg) were added toluene (18 mL) and N,N′-dimethylethylenediamine (387 μL), and the mixture was refluxed for 3 hr. Since the starting materials were left, copper (I) iodide (343 mg) and N,N′-dimethylethylenediamine (387 μL) were added and the mixture was further refluxed for 4 hr. The reaction mixture was cooled, ethyl acetate and aqueous ammonium chloride solution were added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 1:1 mixture of saturated aqueous ammonium chloride solution and ammonia water, and the mixture was washed once with saturated aqueous ammonium chloride solution, once with saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.48 g).
Reaction SMILES: C([O:8][C@H:9]1[C@@:13]2([O:16][CH2:15][CH2:14]2)[C@H:12]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:11][C@@H:10]1[CH2:25][O:26]CC1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]1[C@@:13]2([O:16][CH2:15][CH2:14]2)[C@H:12]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:11][C@@H:10]1[CH2:25][OH:26]
Reactant: O=c1ccn([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@]23CCO3)c(=O)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@]23CCO3)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 9 (50 mg, 0.111 mmol) in methanol (1 mL) and Pd(OH)2 (8 mg) was stirred under a hydrogen atmosphere at room temperature. After 4 hours, more Pd(OH)2 (30 mg) and methanol (1 mL) were added. The mixture was stirred vigorously under H2-atmosphere overnight. The catalyst was removed by filtration over decalite, and the solvent was removed by evaporation. The resulting residue was purified by silica gel chromatography eluted with 10% methanol in ethyl acetate to give the intermediate 10 as white powder (16.8 mg; 56%). HPLC Condition B, Rt: 1.98 min, m/z=271 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 7.65 (d, 1H, J=8.0 Hz), 6.11 (s, 1H), 5.82 (d, 1H, J=8.0 Hz), 4.46-4.61 (m, 2H), 4.06-4.13 (m, 1H), 3.87-3.95 (m, 1H), 3.69-3.77 (m, 2H), 2.62-2.73 (m, 1H), 2.48-2.58 (m, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH:5]N(C)C)[CH:3]=O.[NH:9]([C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[NH2:10].O.Cl>CO>[CH3:5][C:2]1[CH:1]=[N:10][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:3]=1
Reactant: CC(C=O)=CN(C)C
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cnn(-c2nc3ccccc3c(=O)[nH]2)c1
Reaction time: 1.5 h

Procedure:
149.2 g (1.32 moles) of 2-methyl-3-dimethylaminoacrolein are added all at once to a mixture, stirred at 40° C., of 211.2 g (1.2 moles) of 2-hydrazino-4(3H)-quinazolinone, 1.5 litres of water, 540 ml of methanol and 220 ml of concentrated hydrochloric acid. The suspension is stirred at 40° for a total of 4.5 hours and at 60° for 1.5 hours. The crude 2-(4-methyl-1H-pyrazol-1-yl)-4(3H)-quinazolinone isolated at room temperature is obtained in an amount of 245 g of melting point 169°-71°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:27]([C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][N:9]=2)[CH2:4]1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:34]([NH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:27]([C:28]3[CH:33]=[N:32][CH:31]=[N:30][CH:29]=3)=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:23])[F:24])=[CH:17][CH:16]=3)=[O:13])=[CH:10][N:9]=2)[CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-6-(3-(Aminomethyl)pyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Example 177, 30 mg, 0.063 mmol) was dissolved in dioxane (0.5 mL), acetic anhydride (7.09 mg, 0.069 mmol) was added and the RM was stirred for 3 h at RT. The RM was poured into 15 mL of Na2CO3 10%, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure, dissolved in MeOH, evaporated and dried under HV to afford the title compound as an off-white solid. HPLC (Condition 4) tR=4.95 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=517.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.60 (m, 1H) 1.75 (s, 3H) 1.79-1.93 (m, 1H) 2.15-2.31 (m, 1H) 2.86-3.02 (m, 3H) 3.04-3.20 (m, 2H) 3.23-3.36 (m, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.77-7.93 (m, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.77 (d, J=0.78 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6][CH2:7]2.[OH:11]S(O)(=O)=O.CN1C2CCC1CC(=O)C2.[N-]=[N+]=[N-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][C:6](=[O:11])[CH2:7]2
Reactant: CN1C2CCNCC1CC2
Reactant: O=S(=O)(O)O
Agent: CN1C2CCC1CC(=O)C2
Agent: O=C([O-])[O-]
Agent: [N-]=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: CN1C2CCC1CC(=O)NC2
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
9-Methyl-3,9-diazabicyclo[4.2.1]nonane (J. Org. Chem., 1960, 637 ). Conc. H2SO4 (6.25 ml, 0.117 mol) was added dropwise to a stirred cold (−5° C.) solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (2.78 g, 0.02 mol) in CHCl3(25 ml) while keeping the temperature below 15° C. After cooling to 0-5° C., neat sodium azide (2.60 g, 0.040 mol) was added in small portions while maintaining pot temperature below 35° C. The mixture stirred at rt for 2 h and then heated at 50° C. for 2 h. Rxn mixture was poured into ice and neutralized with Na2CO3 and then basify with 50% NaOH. Organic layer separated and the aq. layer re-extracted with CHCl3 (2×25 ml). Combined organic layers were washed with water (10 ml), brine and dried (MgSO4). Evaporation of CHCl3 gave 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one as a off-white solid (1.15 g, 37%). 1H NMR (400 MHz, CHLOROFORM-D) ppm 1.67-1.75 (m, 1H) 1.77-1.85 (m, 1H) 2.05-2.16 (m, 2H) 2.42 (s, 3H) 2.46 (ddd, J=16.05, 6.23, 2.14 Hz, 1H) 2.80-2.90 (m, 2H) 3.17 (t, J=6.42 Hz, 1H) 3.24 (t, J=6.30 Hz, 1H) 3.60 d), J=14.60 Hz, 1H) 5.90 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:42])[CH:29]=[C:28]([O:27][CH3:26])[C:33]=1[O:34][CH3:35]
Reactant: COc1cc(-c2cccc(C(=O)O)c2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cccc(C(=O)N3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (226 mg), 3-(3,4,5-trimethoxyphenyl)benzoic acid (173 mg) and 4-(dimethylamino)pyridine (61 mg) were dissolved in dichloromethane (3 mL), and triethylamine (2.1 μL) was added to the solution. Water-soluble carbodiimide hydrochloride (115 mg) was added to the mixture at 0° C., and the resultant mixture was stirred for 2 hours at 0° C. and overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain the title compound as a free base.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])=[CH2:2].[OH-].[Na+].[CH3:36]I>>[CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:36])=[CH2:2]
Reactant: CI
Reactant: C=COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Product: C=COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A 1-L flask equipped with a stirrer, a dropping funnel, a thermometer, a condenser tube, and a nitrogen gas inlet was charged with 500 parts of decaethylene glycol vinyl ether and 80 parts of sodium hydroxide. The flask was heated to 40° C. with stirring under a nitrogen atmosphere, and then 287 parts of methyl iodide was slowly dropped while the internal temperature was maintained at 40° C. or lower. After completion of the dropping, the mixture was aged for five hours, and distilled under reduced pressure so that unreacted methyl iodide was removed. In order to further remove sodium hydroxide in excess and water and sodium iodide generated after the reaction, adsorption treatment was performed using an adsorbent, and thereby decaethylene glycol methyl vinyl ether was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:27]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)[C@H](C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (R)-(−)-3-hydroxy-2-methylpropionate (0.82 g, 6.92 mmol) (Aldrich) was dissolved in dichloromethane (8 mL, dried over molecular sieves). Imidazole (0.67 g, 9.68 mmol) (Aldrich) was added. When all had dissolved, tert-butyldiphenysilyl chloride (1.80 mL, 6.92 mmol) (Aldrich) was added and the mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give methyl (R)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionate as an oil. (Yield 2.42 g, 98%).
Reaction SMILES: F.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Reactant: OB(O)c1ccco1
Agent: F
Product: Nc1ncc(-c2cccc(Nc3ccc(-c4ccco4)cc3[N+](=O)[O-])c2)cn1

Procedure:
N-(3-(2-Aminopyrimid-5-yl)phenyl)-4-(2-furanyl)-2-nitroaniline (7p) was prepared analogously from 6l (Example 10) and 2-furanylboronic acid in quantitative yield. Mp 178-180° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[C:10]([NH2:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[CH2:10][NH2:12]
Reactant: NC(=O)C1Oc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzo[1,3]dioxole-2-carboxylic acid amide (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1M in THF, 39.5 mL, 39.5 mmol) was added slowly to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy the excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted with ethyl acetate (3×100 mL). The combined organic solution was washed with water and dried over MgSO4. The solvent was evaporated to yield C-benzo[1,3]dioxol-2-yl-methylamine as a colorless oil.