Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(C)CC1=C2c3ccc(O)cc3CCC2CCNC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 7.5 g of the slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one (Example 1) in 125 ml of methylene chloride is added slowly to 125 ml of a stirred 10 percent solution of boron tribromide in methylene chloride, precooled in a dry ice-acetone bath. The mixture is allowed to warm to room temperature slowly and is stirred overnight. It is cooled in an ice bath, 100 ml of water and 100 ml of 3 N aqueous sodium hydroxide are added and stirring is continued for one half hour. The basic aqueous solution is separated, washed with diethyl ether, neutralized to pH=8-9 with hydrochloric acid and allowed to stand overnight. The product, collected by filtration and subsequent extraction with chloroform, is suspended in 5 percent aqueous sodium bicarbonate and the suspension is stirred for 4 hours. The insoluble product is collected, dried and recrystallized from ethanol, to yield 1-(2-isopropylaminopropyl)-9-hydroxy-3,4,5,5a,6,7-hexahydro- 2H-naphth[1,2-d]azepin-2-one as a single diastereoisomer, melting at 202°-204°.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:5]=2[CH:4]=[N:3][C:2]=1[NH:20][CH:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.Cl>O1CCOCC1>[NH:24]1[CH2:23][CH2:22][CH:21]([NH:20][C:2]2[N:3]=[CH:4][C:5]3[C:11]4[CH:12]=[CH:13][N:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C:6]=3[N:1]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(n2)-c2cccnc2Nc2cnccc2-3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cnc2c(c1)-c1nc(NC3CCNCC3)ncc1-c1ccncc1N2

Procedure:
The compound, N-(piperidin-4-yl)-9H-dipyrido[2,3-b:4′,3′-f]pyrimido[4,5-d]azepin-2-amine was synthesized using three step procedure shown above. The first two steps provided the intermediate, tert-butyl 4-((9H-dipyrido[2,3-b:4′,3′-f]pyrimido[4,5-d]azepin-2-yl)amino)piperidine-1-carboxylate, which was prepared using 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one and 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)guanidinium chloride as described in the General procedure A. The desired compound, N-(piperidin-4-yl)-9H-dipyrido[2,3-b:4′,3′-f]pyrimido[4,5-d]azepin-2-amine was obtained by treating tert-butyl 4-((9H-dipyrido[2,3-b:4′,3′-f]pyrimido[4,5-d]azepin-2-yl)amino)piperidine-1-carboxylate with a solution of HCl (gas) in 1,4-Dioxane (3 mL) for 4 hour. The solvent was then removed under reduced pressure and the crude product was purified using reverse phase chromatography to give the desired product as yellow solid and a TFA salt (0.025 g, 40%); M.p.=189-191° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.71 (bs, 2H), 8.58 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.29-8.26 (m, 2H), 7.88 (bs, 1H), 7.52-7.51 (d, J=5.4 Hz, 1H), 7.13-7.10 (m, 1H), 4.19 (bs, 2H), 3.40-3.39 (bd, 1H), 3.21-3.18 (bd, 1H), 2.86-2.53 (m, 2H), 1.98-1.57 (m, 4H); LCMS (M+H)=346.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16][CH2:17]O>>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:16][CH3:17])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncccc1N
Reaction time: 120 h

Procedure:
A solution of 3-aminopicolinic acid (5.00 g, 36.2 mmol) in EtOH (70 mL) and concentrated sulfuric acid (6.0 mL, 110 mmol) was heated to 100° C. and stirred for 5 days. The cooled mixture was concentrated to −20 mL and poured over ice. This mixture was treated with aqueous ammonia (NH4OH, conc) until pH>7. This was extracted twice with 100 mL EtOAc. The basified aqueous layer was saturated with salt and extracted again with 2× 100 mL EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to 4.15 g of an off white solid (69%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.07 Hz, 3H), 4.27 (q, J=7.07 Hz, 2H), 6.67 (br. s., 2H), 7.17-7.22 (m, 1H), 7.24-7.29 (m, 1H), 7.84 (dd, J=4.04, 1.52 Hz, 1H). MS (ES+): m/z=167.06 (100) [M+1]. HPLC: tR=2.76 min (ZQ3, vvpolar—5 min).
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([CH2:47][CH3:48])=[CH:25][CH2:26][C:27]1[C:35]([O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])=[C:34]2[C:30]([CH2:31][O:32][C:33]2=[O:43])=[C:29]([CH3:44])[C:28]=1[O:45][CH3:46].[Cl-].[NH4+]>C1COCC1>[CH2:6]([O:5][P:4]([CH:3]([C:1]#[N:2])[CH2:23][C:24]([CH2:47][CH3:48])=[CH:25][CH2:26][C:27]1[C:35]([O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])=[C:34]2[C:30](=[C:29]([CH3:44])[C:28]=1[O:45][CH3:46])[CH2:31][O:32][C:33]2=[O:43])(=[O:11])[O:8][CH2:9][CH3:10])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C#N)CC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (233 mg, 1.32 mmol) in THF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide (1.0 M, 1.21 mL, 1.21 mmol). After stirring for 30 minutes, the solution was added dropwise to a solution of 6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (100 mg, 0.22 mmol) in THF (1 mL). The resulting mixture was allowed to stir at room temperature overnight before saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC, affording 51 mg (42%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.07 (t, 3H), 1.24 (dd, 2H, J=7, 8 Hz), 1.36 (t, 6H), 2.12 (m, 1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67 (m, 1H), 3.00-3.14 (m, 1H), 3.44 (d, J=7.2, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.38 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 18.26 ppm; MS (m/z) 574 [M+Na]+.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22]C2CCCCO2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCCOC2CCCCO2)cc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCC(Cc1ccc(OCCCO)cc1)C(=O)OCC
Yield: 87 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-butyl-3-[4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl]propionate (4.42 g) and p-toluensulfonic acid monohydrate (2.57 g) and the reaction mixture was treated to afford the desired compound (3.02 g) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][CH:13]=[CH:12][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([CH3:21])[C:9]1=[O:22])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:7][C@H:8]1[CH2:14][CH:13]=[CH:12][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([CH3:21])[C:9]1=[O:22]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC=C[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To the tert-butyl[(3S,7S)-1-methyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (1d) (200 mg) was added a 1:3 mixture of TFA/DCM (2 ml). The reaction mixture was stirred for 1 h, then diluted with DCM and saturated aq. NaHCO3. The organic layer was isolated and washed with saturated aq. NaHCO3, brine, dried (Na2SO4) and concentrated to yield an oil (128 mg, 93%). MS APCI, m/z=217 (M+1). LC/MS 1.55 min., Method A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH3:11])[N:10]=[C:4]2[CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH:32]([OH:33])[C:30]3[CH:29]=[CH:28][C:22]4/[C:23](=[C:24](/[CH3:27])\[C:25]#[N:26])/[C:17]5[CH:16]=[CH:15][C:14]([F:13])=[CH:34][C:18]=5[O:19][CH2:20][C:21]=4[CH:31]=3)=[C:9]([CH3:11])[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1nc2cc(Cl)ccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4cc(Cl)ccn34)cc2COc2cc(F)ccc21
Yield: 85.3 %

Procedure:
[step 3] Using 7-chloro-3-iodo-2-methylimidazo[1,2-a]pyridine (700 mg, 2.39 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (351 mg, 1.20 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[7-chloro-2-methylimidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (471 mg, 86%) was obtained.
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15]>>[C:14]([CH2:16][C:17]([NH:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9])=[O:18])#[N:15]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: N#CCC(=O)O
Solvent: O
Product: Cn1c(N)c(NC(=O)CC#N)c(=O)n(C)c1=O

Procedure:
5,6-Diamino-1,3-dimethyluracil hydrate is reacted with cyanoacetic acid to yield 5-cyanoacetamido-6-amino-1,3-dimethyluracil of the formula: ##STR4## The 5-cyanoacetamido-6-amino-1,3-dimethyluracil is treated with sodium hydroxide within a temperature range of 145°-155° C. to yield 8-carboxymethyltheophylline of the formula: ##STR5## The 8-carboxymethyltheophylline is treated with an alkylated inhibitor of the formula: ##STR6## to yield the compounds of formula (II).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:29]=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.P([O-])(O)(O)=[O:33].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCCCCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[C:29]([OH:33])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=P([O-])(O)O
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC4CCCC4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.1 %

Procedure:
To a stirred solution of afforded 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (200 mg, 0.49 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (184 mg, 1.33 mmol), 2-methyl-2-butene (0.226 mL, 2.00 mmol) and sodium chlorite (181 mg, 2.00 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate and hexane to afford 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (120 mg, 58% yield) as a yellow solid: HR-MS m/e calcd for C24H23N1O6 (M−H+) 421.1525, found 421.1526; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[S:30]([CH2:29][CH2:28][N:19]2[C:18](=[O:17])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:27])(=[O:31])=[O:32])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: CC(C)N1CCC(NCc2nccs2)CC1
Product: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide was prepared by an analogous procedure as described for example 1 i) starting from 217 mg (0.91 mmol) (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amine and 250 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. Purification by flash chromatography on silica gel (eluent: CH2Cl2/MeOH) gave pure 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide as a light yellow foam. Yield: 178 mg MS (ES+): m/e=477.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=C[C@H]4O)CC2)C)OC1>>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[C@H:15]([O:31][C:32](=[O:35])[NH:33][CH3:34])[CH:16]=3
Reactant: CNC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CNC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C=O)CC[C@H]3[C@H]12
Yield: 62.3 %

Procedure:
The procedure of Example 36 was repeated except that 2.5 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol to give 1.3 mg of 1α,2α-epoxy-3β-hydroxy-7α-(N-methylcarbamoyloxy)pregn-5-ene-20-carbaldehyde (yield: 62%).
Reaction SMILES: C(OC([N:8]([CH2:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH3:28])[CH2:9][CH3:10])=O)(C)(C)C.Cl>CO>[CH2:27]([NH:26][CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:8][CH2:9][CH3:10])[CH3:28]
Reactant: CCN(CCCN(CCCCCCCN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNCCCNCCCCCCCNCCCNCC
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Treat 3,7,15,19-tetra(t-butoxycarbonyl)-3,7,15,19-tetraazaheneicosane (1.68 gm, 0.0024 mol) with HCl in methanol (50 ml, 1.0N) and stir overnight. Filter the mixture and recrystallize the title compound from methanol/water (20:80, v/v) to yield 0.5 gm of the title compound. Rf is 0.39 on silica gel plates eluted with 40% ammonia (concentrated) in methanol; mp 322°-23° C. with degradation.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([N:51]3[CH2:52][CH2:53][C:48]([F:54])([F:47])[CH2:49][CH2:50]3)=[O:14])=[CH:11][C:6]2=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3nc2Cl)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3nc2Cl)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 1 from 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 4,4-difluoro-piperidine and N,N-diisopropylethylamine in DMF to give the desired product as a light yellow foam (40%).
Reaction SMILES: [OH:1][CH:2]([CH3:22])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4].[H-].[Na+].I[CH3:26]>C1COCC1.C(OCC)(=O)C>[CH3:26][O:1][CH:2]([CH3:22])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4]
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.33 h

Procedure:
To a suspension of tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-indole-3-carboxylate (500 mg, 1.65 mmol) in THF (8 mL) was added sodium hydride (330 mg, 8.25 mmol) at 30° C. under N2. The reaction was stirred for 20 min. Then iodomethane (0.4 mL) was added and the reaction was stirred at 60° C. for 3 hrs. Then the mixture was diluted with ethyl acetate, washed with water and saturated aqueous NaHCO3. The crude product was purified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate=80:1 to afford the title compound as a yellow solid which was used directly (400 mg, 76.8%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2cccnc2)CCc2ccc(Br)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1c2cc(Br)ccc2CCC1Cc1cccnc1
Yield: 85.8 %

Procedure:
A solution of 7-bromo-2-(3-pyridylmethylene)-1-tetralone (13.9 g) in ethanol (150 ml) containing 5% palladium on charcoal (0.50 g) was hydrogenated at 25° and 4 atm. pressure until the theoretical quantity of hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated. The residue was distilled to give an oil (12.0 g), b.p. 200°-240° at 1.0 mm containing ca 40% of debrominated material. The product was purified by high pressure liquid chromatography using a silica gel column and a mixture of hexane and ethyl acetate (45:55) as eluent. Debrominated product was eluted first followed by pure 7-bromo-2-(3-pyridylmethyl)-1-tetralone, m.p. 63°-67°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Nc1ccnc(Cl)n1
Product: Nc1ccnc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)n1

Procedure:
EXAMPLE 96 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-pyrimidin-4-ylamine (prepared from 2,4-chloro-pyrimidin-4-ylamine by hydrogenation in ethanol over 5% palladium on carbon, 1 atm of hydrogen): MS (m+1)=376.5.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:19][CH2:18]3)=[O:16])[O:12][C:11]2=[O:30])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[ClH:31]>>[ClH:31].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)=[O:16])[O:12][C:11]2=[O:30])=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(C(=N)N)cc3)C(=O)O2)CC1
Agent: Cl
Product: N=C(N)c1ccc(N2CC(C(=O)N3CCC(C(=O)O)CC3)OC2=O)cc1
Temperature: 25 °C

Procedure:
0.41 g of tert-butyl 1-[3-(4-amidinophenyl)-2-oxo-5-oxazolidinylcarbonyl}piperidin-4-yl-carboxylate is stirred in 40 ml of ethereal HCl solution at room temperature for 2 h. The precipitate formed is filtered off with suction and washed with 20 ml of ether. The product is then treated with 5 ml of acetonitrile at 60° for 10 min, the mixture is cooled to room temperature, and the product is filtered off with suction and washed with a little acetonitrile. 1-[3-(4-amidinophenyl)-2-oxo-5-oxazolidinylcarbonyl]piperidine-4-carboxylic acid, hydrochloride, m.p. 184° (decomposition), is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](O)([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])C)C.[CH3:14]I.Cl>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH3:14][CH2:12][CH:10]=[CH:9][CH2:8][CH2:7][CH2:5][CH2:4][CH3:3]
Reactant: CI
Reactant: CCC(C)(O)CCC=C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC=CCCCCC
Temperature: 37.5 °C
Reaction time: 8 h

Procedure:
To a dry 2 L multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an additional funnel, 400 ml of THF, 44 g of NaH, and 21.2 g of dihydroethyl linalool were added and heated to 35-40° C. 170 g of dihydrolinalool g was then added to the reaction mixture dropwise over 2 hours. The mixture was aged for 8 hours. 9 g of HMPA (available from Aldrich Chemical Company) was added and the mixture was stirred. 144 g of CH3I was added dropwise to the reaction mixture, further aged for two hours and then sampled hourly until maximum conversion was reached. The mixture was cooled and 800 ml of 5% HCl solution was added, allowed to settle, and the organic layer was separated. The aqueous layer was extracted with 3×100 ml of toluene and then dried over MgSO4 to provide 3-nonene, 7-methoxy-3,7-dimethyl-.