Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17](S(C)(=O)=O)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:9]=2[C:8]1=[O:31].[C:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])[CH3:42]>>[C:41]([N:44]1[CH2:49][CH2:48][N:47]([CH:12]2[N:11]([CH3:15])[C:10]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])[C:9]=3[C:8](=[O:31])[N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=3)[CH2:14][CH2:13]2)[CH2:46][CH2:45]1)(=[O:43])[CH3:42]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C2CCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)c3c(-c4ccccc4C)ncnc3N2C)CC1
Yield: 82.6 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 21; 88.0 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 9-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (78.6 mg, 83%).
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[S:7][CH:8]=[C:9]([CH:11](O)[CH3:12])[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]([Br:3])[CH3:12])[N:10]=1
Reactant: O=S(Br)Br
Reactant: CC(O)c1csc(Br)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a stirred solution thionyl bromide (0.787 g, 3.78 mmol, 1.05 eq.) in 20 ml dry DCM, cooled to 5° C., was added dropwise a solution of 1-(2-bromo-1,3-thiazol-4-yl)ethanol (0.75 g, 3.60 mmol, 1 eq.) and pyridine (0.285 g, 3.60 mmol, 1 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 100 ml of water and 100 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried of MgSO4 and evaporated to give 2-bromo-4-(1-bromoethyl)-1,3-thiazole (0.9 g, 84% yield) as a yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:17]2[CH:16]=[CH:15][C:14]([NH2:19])=[C:13]([O:12][CH3:11])[CH:18]=2)=[CH:4][N:3]=1
Reactant: COc1ccccc1N
Reactant: Nc1ncc(CO)c(N)n1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A solution of 6.30 g (0.045 mol) of 2,4-diamino-5-hydroxymethylpyrimidine, 6.15 g (0.05 mol) of o-anisidine and 3.75 ml of concentrated hydrochloric acid in 55 ml of glacial acetic acid was heated to reflux for 6 hours. The mixture was stirred at room temperature overnight. The solvent was removed under vaccum and the residue was taken up in water, made basic with ammonium hydroxide, and the aqueous solution was extracted with dichloromethane:methanol/3:1. The organic layers were combined, dried and concentrated to a purple glass. This was purified on a silica gel column to give 7.81 g of the 4-N-acetylated product.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide (Intermediate 9, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3-chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 475) in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=8.7 Hz, 2H), 7.91 (s, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.41 (m, 1H), 7.38 (m, 1H), 5.65 (s, 2H), 4.51 (t, J=6.6 Hz, 2H), 2.70 (br s, 1H), 1.87 (t, J=6.6 Hz, 2H), 1.20 (s, 6H); MS (DCI/NH3) m/z 463 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:9]=1)([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:9]=1
Reactant: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.6 %

Procedure:
To a solution of methyl 3-[(5-nitropyridin-2-yl)oxy]benzoate (14.4 g, 52.5 mmol) in methanol (100 mL) was added palladium carbon (50% water-containing product, 1.40 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (12.9 g, quant.) as a yellow oil.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38])[CH3:28].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:27][CH3:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: CCc1ccccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
PS-DCC (962 mg, 1.37 mmol, loading: 1.33 mmol/g) is suspended in THF (10 mL). HOBT (210 mg, 1.37 mmol), (2-ethyl-phenylamino)-phenyl-acetic acid hydrochloride (I60) (200 mg, 0.68 mmol), and (R)-quinuclidin-3-ol (262 mg, 2.06 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and washed with THF and the filtrate is evaporated under reduced pressure. The resulting residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is separated, dried over Na2SO4, filtered and evaporated. The residue is first purified by flash chromatography (DCM/MeOH=9/1) and then by preparative HPLC. The fractions containing the product are pooled, concentrated under vacuum, basified with sat. NaHCO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as a colorless oil (52 mg, 21% yield, mixture of diastereoisomers).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([NH2:64])[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:58]5[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and piperidin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.90 (m, 16 H) 3.16 (br. s., 6 H) 3.32 (s, 3 H) 3.96 (s, 3 H) 4.14 (t, 2 H) 4.48 (quin, 1 H) 7.47 (d, 1 H) 7.49 (s, 1 H) 8.22 (d, 1 H) 8.24 (s, 1 H) 8.47 (br. s., 1 H). [M+H] calc'd for C27H35F2N7O3 544; found 544.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([B:29]([OH:34])[OH:30])[C:25]([F:28])=[CH:24][N:23]=1
Reactant: Fc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1cc(F)ncc1F
Temperature: -20 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Diisopropylamine (1.74 ml, 1.24 g, 12.20 mmol) was dissolved in anhydrous THF (22 ml) and placed under argon. The solution was cooled to −20° C. and then treated with n-butyllithium (7.66 ml, 12.25 mmol, 1.6 M in hexanes) by slow addition over 10 min. The newly formed LDA (LDA= lithium diisopropylamide, this acronyl should be listed in the general session) was then cooled to −78° C. and treated with a solution of 2,5-difluoropyridine (1.05 ml, 1.33 g, 11.56 mmol) dissolved in anhydrous THF (3 ml) by slow addition over 30 min. Once the addition was complete the reaction mixture was allowed to stir at −78° C. for 4 hr. At this time the reaction mixture was treated with a solution of triisopropyl borate (5.90 ml, 4.78 g, 25.4 mmol) dissolved in anhydrous THF (8.6 ml) by dropwise addition. Once the addition was complete the reaction mixture was allowed to warm to ambient temperature then stirred at ambient temperature for an additional hour. The reaction mixture was then quenched by adding 4% aq NaOH (34 ml). The layers were separated and the aqueous layer was cooled in an ice bath. It was then acidified to pH= 4 with 6N HCl (˜10 ml) not letting the temperature go above 10° C. This was then extracted with EtOAc (3×50 ml). The extracts were then washed with brine (1×50 ml), dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was triturated with Et2O to give 0.8084 g (44%) of 2,5-difluoropyridin-4-ylboronic acid.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][OH:12])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]=O>FC(F)(F)C(O)=O>[OH:12][CH2:11][CH2:10][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][O:9][CH2:8]1
Reactant: OCCC(CO)(c1ccccc1)c1ccccc1
Reactant: C=O
Solvent: O=C(O)C(F)(F)F
Product: OCCC1(c2ccccc2)COCc2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In trifluoroacetic acid (50 ml) was dissolved 2,2-diphenyl-1,4-butanediol (5 g) followed by addition of paraformaldehyde (1.7 g) and the mixture was heated and stirred at 50° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) followed by addition of sodium hydroxide (4 g) and water (50 ml) and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using isopropyl ether/ethyl acetate as the eluent to provide 4-(2-hydroxyethyl)-4-phenylisochroman (4.5 g).
Reaction SMILES: CCN(CC)CC.[C:8]([O:11][CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)=O)(=[O:10])[CH3:9].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl>CCO>[C:8]([O:11][CH2:12][C:13]1[N:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:30]=[C:16]2[C:15]=1[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])[CH3:9]
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)OCC(=O)C1CCCCC1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c2c(nn1-c1ccc(F)cc1)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Et3N (0.717 mL, 0.520 g, 5.14 mmol) was added to a stirring suspension of 1.00 g (5.04 mmol) of 2-acetoxyacetylcyclohexanone (Dolmazon, R.; Gelin, S. J. Heterocyclic Chem., 1982, 19, 117-121) and 0.820 g (5.04 mmol) of 4-fluorophenylhydrazine·HCl in 20 mL of absolute EtOH. The resulting solution was stirred under N2 for 4 h at room temperature and refluxed for 6 h. The mixture was concentrated and the residue was partitioned between 100 mL of Et2O and 50 mL of dilute aqueous HCl. The Et2O layer was washed with water, saturated aqueous NaHCO3, and brine. After drying over Na2SO4, the solution was concentrated to give 1.43 g of light brown solid. Recrystallization from EtOAc:hexanes afforded 0.753 g (52%) of the title compound as a white solid, m.p. 128.5°-129.5° C.; 1H NMR (CDCl3, 400 MHz) 1.85 (m, 4), 2.07 (s, 3), 2.60 (t, 2, J=6 Hz), 2.73 (t, 2, J=6 Hz), 5.00 (s, 2), 7.15 (t, 2, J=9 Hz), 7.45 (dd, 2, J=5, 9 Hz); IR (KBr) 1740, 1220 cm-1 ; MS (DCI) m/z 289 (base), 228 . Anal. Calcd. for C16H17FN2O2 : C, 66.65; H, 5.94; N, 9.72. Found: C, 66.74; H, 5.89; N, 9.61.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(#N)C.[CH:12]1([C:18]2[CH:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Br:1][C:19]1[C:20]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:21][C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:23][C:18]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: Brc1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Temperature: 25 °C
Yield: 81 %

Procedure:
A 500-mL three-neck flask was charged with 15.7 g of N-bromosuccinimide and 100 g of acetonitrile. Under ice cooling, a dilute solution of 28.4 g of 1,3,5-tricyclohexylbenzene (prepared by known reaction) in 60 g of methylene chloride was added dropwise over 30 minutes. The solution was warmed to room temperature and aged for 12 hours. The resulting crystal precipitate was filtered, washed with acetonitrile and water, and dried, obtaining the target compound, 2-bromo-1,3,5-tricyclohexylbenzene as white crystal. Amount 28.4 g, yield 81%.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A solution of 4-[1-(1-cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours. The solvents were removed in vacuo. The resulting residue was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (30 mg, 60%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16]1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)=[CH:16]1
Reactant: OCc1ccoc1
Reactant: Clc1nc(SCc2ccccc2)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nsc(OCc3ccoc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To 2 g of N,N-dimethylformamide, 0.243 g of 5-chloro-3-benzylthio-1,2,4-thiadiazole and 0.098 g of 3-furanmethanol were dissolved, and added 0.045 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 1 hour and at room temperature for 2 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 0.17 g of 5-(3-furyl)methoxy-3-benzylthio-1,2,4-thiadiazole.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]4[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:25][C:23]4=3)[C:18](=[O:36])[CH:17]=[CH:16]2)[CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[N:15]1[C:24]2[C:19](=[CH:20][N:21]=[C:22]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:25][C:23]3=2)[C:18](=[O:36])[CH:17]=[CH:16]1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1n1ccc(=O)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCNC[C@@H]1n1ccc(=O)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Reaction time: 5 h
Yield: 95 %

Procedure:
rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (98 mg, 0.20 mmol) and 5% palladium-carbon (65 mg) in methanol (2 mL) were stirred at room temperature for 2 hours under a hydrogen atmosphere, then at 40° C. for 5 hours and at room temperature for one day. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow amorphous (76.8 mg, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](Cl)=[O:14])[CH:8]=2)[N:3]=1.[BH4-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][OH:14])[CH:8]=2)[N:3]=1
Reactant: O=C(Cl)c1ccc2nc(Cl)c(Cl)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc2nc(Cl)c(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 25.3 g portion of 2,3-dichloroquinoxaline-6-carbonyl chloride synthesized in accordance with the procedure disclosed in JP-A 57-98274 in 400 ml of anhydrous 1,4-dioxane, was added 14.0 g of sodium borohydride, and the mixture was stirred at room temperature for 10 minutes in an atmosphere of nitrogen. With cooling on an ice bath, to this was added dropwise 100 ml of water. Thereafter, 1,4-dioxane was evaporated under a reduced pressure, and the resulting residue was purified by chromatography on a silica gel column (eluent, hexane/ethyl acetate) to obtain 8.75 g of 2,3-dichloro-6-hydroxymethylquinoxaline.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:12]Br.C(OCC)C>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(N)c1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(N)c(C#N)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Amino-4-methoxybenzonitrile (4.47 g, 30.2 mmol) is dissolved in 70 ml of dioxane and treated at 0° C. with bromine (1.71 ml, 33.2 mmol). It is subsequently stirred at 0° C. for one hour. After addition of diethyl ether, the resulting crystals are filtered off with suction. The desired product is obtained in 81% yield (5.52 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[N:5][NH:4]1)[CH3:2].[C:18]1([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:31](=[O:32])[CH2:30][CH2:29][C:25]3[CH:26]=[N:27][O:28][C:24]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:6]=[N:5][NH:4]1)[CH3:2]
Reactant: CCN1NN=CC1CCOc1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN1NN=CC1CCOc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (1.12 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.04 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.89 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.11 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (1.58 g, yield 76%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 167–168° C.