Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH3:36])[C:13]([SiH2:16][O:17][C@@H:18]1[C:22]([CH2:25][OH:26])([CH2:23][OH:24])[O:21][C@@H:20]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:19]1)([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[CH3:11][CH:12]([CH3:36])[C:13]([SiH2:16][O:17][C@@H:18]1[C@@:22]([CH:23]=[O:24])([CH2:25][OH:26])[O:21][C@@H:20]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:19]1)([CH3:14])[CH3:15]
Reactant: Cc1cn([C@H]2C[C@H](O[SiH2]C(C)(C)C(C)C)C(CO)(CO)O2)c(=O)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2C[C@H](O[SiH2]C(C)(C)C(C)C)[C@@](C=O)(CO)O2)c(=O)[nH]c1=O
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
To a solution of oxalylchloride (0.575 mL, 6.5 mmole) in dichloromethane (10 mL) at -70° C., was added dimethylsulfoxide (0.47 mL, 6.5 mmole). The mixture was stirred at -70° C. for 30 minutes before a solution of Compound (1) (2.4 g, 6.2 mmole) in dichloromethane (18 mL) wasadded. Stirring at -70° C. was continued for 150 minutes. Triethylamine (4.3 mL, 31 mmole) was added dropwise and the reaction mixture was allowed to warm to room temperature over a 20 hour period. Thereaction was quenched by the addition of methanol (2 mL), followed 10 minutes later by 60 mL of water. The phases were separated. The aqueous phase was extracted three times with dichloromethane (60 mL each). The combined organic extracts were washed with solutions of dilute hydrochloric acid followed by saturated sodium bicarbonate and brine. After drying the organic extracts over magnesium sulfate, the solvent was removed under reduced pressure to provide 3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-formyl-thymidine (1.88 g) in crude form as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[CH3:23][C:24]1[C:33]2[CH:32]=[N:31][C:30](S(C)=O)=[N:29][C:28]=2[N:27]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=2)[C:26](=[O:48])[CH:25]=1.CCN(C(C)C)C(C)C.O1CCOCC1>C(O)(C)(C)C>[CH3:22][O:21][C:3]1[CH:4]=[C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:30]1[N:31]=[CH:32][C:33]2[C:24]([CH3:23])=[CH:25][C:26](=[O:48])[N:27]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[C:28]=2[N:29]=1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCNCC5)cc4OC)nc32)c1
Temperature: 90 °C

Procedure:
To a suspension of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (18a, 539 mg, 1.753 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b, 432 mg, 1.173 mmol) in tert-butanol (15 mL) at RT was added DIEA (0.61 mL, 3.52 mmol) followed by dioxane (6 mL). The reaction mixture was heated in a heating block at 90° C. for 20 h. LC-MS analysis indicated roughly 13% conversion to the desired product along with unreacted starting materials. The reaction mixture was concentrated on the rotovap and the crude residue was suspended in Et2O and filtered. The greenish brown amorphous solid was washed with Et2O (3×20 mL) and this removed most of the aniline starting material (18a). The crude material contained roughly 19% of the desired product (18b) along with recovered 5b. m/z (ESI, +ve ion) 611.9 (M+H)+. The crude residue was used in the subsequent step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4](OCC1C=CC=CC=1)[CH2:5][N:6](N=C=O)[C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:31])[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:10]1)=[O:8]>CO.[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:6][C:7](=[O:8])[CH3:9])[C:3]([OH:2])=[O:43])=[O:8])[CH2:10]2)=[O:31])[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](CN(N=C=O)C(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 197.2 %

Procedure:
A mixture of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxy-carbonylamino-β-alanine methyl ester (20 g) and 10% Pd on carbon (50% wet) (5 g) in methanol (500 ml) was stirred vigorously under a hydrogen atmosphere (1 atm) at room temperature. After 2 hours, the insolved material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (200 ml), and cooled to 0° C. 1N aqueous LiOH (116 ml) solution was added to the solution within 15 minutes at 0-3° C. After the mixture was stirred for 45 minutes at 0° C., acetic anhydride (6.89 ml) was added to the mixture within 15 minutes at 0-4° C. The mixture was stirred for 30 minutes at 0° C., then diethyl ether (150 ml) was added. The aqueous layer was separated, and the pH of it was adjusted to 2.5 with aqueous 20% KHSO4 , then extracted with ethyl acetate. The extract was dried over Na2SO4, and concentrated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine (16.3 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3nnsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.13 mmol) in CH2Cl2 (5 mL) was added triethylamine (26 mg, 0.25 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (26 mg, 0.19 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.75-7.72 (d, 2H), 7.35 (m, 1H), 3.35 (m, 1H), 1.70 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([C:13]#[N:14])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].ClC1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:9]([CH:8]1[CH2:7][C:6]([C:13]#[N:14])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:5][CH2:4][C:3]1=[O:22])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccccc2Cl)CCC1=O
Yield: 95 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 39.11 gm. (0.121 mole) dimethyl-4-(o-chlorophenyl)-4-cyanopimelate (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, and using 780 ml. of the tetrahydrofuran, 27.4 gm. (0.24 mole) of the potassium tert-butoxide, and 195 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 33.4 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(o-chlorophenyl)cyclohexanone as a crystalline solid having a melting range of 113° to 118° C.
Reaction SMILES: [CH2:1]([C:13]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:23]2[CH:22]=[CH:21][S:20][C:19]=2[C:15]2[S:16][CH:17]=[CH:18][C:14]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])(C)(C)C.[CH3:41][Sn:42](Cl)([CH3:44])[CH3:43].O>C1COCC1.CCCCC>[CH2:24]([C:13]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2[CH:18]=[C:17]([Sn:42]([CH3:44])([CH3:43])[CH3:41])[S:16][C:15]=2[C:19]2[S:20][C:21]([Sn:42]([CH3:44])([CH3:43])[CH3:41])=[CH:22][C:23]1=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2ccsc2-c2sccc21
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2cc([Sn](C)(C)C)sc2-c2sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A dry three-neck round bottom flask was equipped with a Schlenk adapter, dropping funnel, and rubber septum. Under nitrogen, 4,4-didodecyl-4H-cyclopenta[1,2-b:5,4-b′]dithiophene (0.51 g, 1 mmol) was dissolved in dry THF (12 ml) and cooled −78° C. using a dry ice/acetone cold bath. Under nitrogen, a solution of t-butyllithium (1.7 M in pentane, 2.35 ml, 4 mmol) was added dropwise over 15 minutes to the reaction vessel. The reaction was stirred at −78° C. under nitrogen for one hour and stirred at room temperature for 3 hours. Under nitrogen, a solution of trimethyltin chloride (1.0 g, 5 mmol) in dry pentane (2 ml) was added dropwise over 5 minutes to the reaction vessel at −78° C. The reaction was stirred at −78° C. under nitrogen for 1 hour and subsequently warmed to room temperature and stirred overnight. The mixture was then poured into deionized water (3×100 ml) and the organic phase extracted with hexanes (3×50 ml). The organic phases were collected and washed with deionized water (3×50 ml), dried over sodium sulphate, filtered, and concentrated. The product was dried under high vacuum with agitation for 48 hours to give 0.80 g of product as colorless oil, yield 95%. 1H NMR (500 MHz, CD2Cl2) δ (ppm): 6.94 (s, 2H), 1.79-1.76 (m, 4H), 1.29-1.15 (m, 36H), 1.08-1.02 (m, 4H), 0.88 (t, J=6.0 Hz, 6H), 0.39 (s, 18H).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:6]=[CH:7][C:8]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])=[C:9](/[CH:11]=[CH:12]/[CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)[CH:10]=1.Cl>C1COCC1.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:13](/[CH:12]=[CH:11]/[C:9]2[CH:10]=[C:5]([F:4])[CH:6]=[CH:7][C:8]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:32][CH:31]=1)([OH:35])=[O:34]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.57 mg (61.3 mmol) of lithium hydroxide monohydrate are added to a solution of 12 mg (10.4 μmol) of methyl 4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate (Example 29A) in 0.3 ml of THF and 0.3 ml of water, and the mixture is stirred at room temperature for 16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 5.0 mg (8.93 μmol, 43.8% of theory) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[CH3:12][NH2:13].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:13][CH3:12])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: COc1cnc(SC)nc1Cl
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CNc1nc(SC)ncc1OC

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-methoxy-pyrimidine by reacting with methylamine in ethanol at 90° C., Rf value: 0.22 (silica gel; cyclohexane/ethyl acetate=2:1)
Reaction SMILES: O1CCCC1.[CH:6]([O:9][C:10](=[O:33])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].[S].[H][H]>[Pt].CC(O)C>[CH:6]([O:9][C:10](=[O:33])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Pt]
Agent: [S]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)OC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 10 °C

Procedure:
To 80 mL of tetrahydrofuran, there was added 31.3 g (content: about 50 wt %) of the wet crystals of Nα-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine isopropyl ester at room temperature in a nitrogen gas atmosphere and the mixture was then stirred. To the mixture, there were added 80 mL of 2-propanol and 0.86 g of 3% Pt—S/C (wet product, obtained by applying platinum onto carbon and then poisoning the same with sulfur), hydrogen gas was then introduced into the reaction system and the reaction system was stirred at ordinary pressure. The reaction system was stirred at room temperature overnight as it was, and then the catalyst was removed from the reaction solution by filtration through Celite after the confirmation of the progress of the reaction according to HPLC. The resulting filtrate (initial amount of 178 g) was concentrated by distilling the solvent off under reduced pressure till the amount of the filtrate reached 91 g and 40 mL of 2-propanol was added to the concentrate to thus adjust the concentration of the condensate. To this liquid whose concentration had been adjusted, there was dropwise added 150 mL of water at room temperature to thus separate out a crystalline solid and the resulting suspension was maintained at a temperature of not higher than 10° C. overnight. The resulting crystals were filtered off, washed with 100 mL of water and the resulting wet crystals were dried at 60° C. under reduced pressure to thus give 13.16 g of the title compound as a white crystalline solid (overall yield of these two steps: 86%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12](Cl)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2].[CH3:23][NH:24][CH3:25]>>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Reactant: CNC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N(C)C)c2Cl)c1O
Temperature: 110 °C

Procedure:
A mixture of 0.60 g (1.7 mmol) of 1-ethyl-4-(2,3-dichloro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole and 8 mL of 40 percent aqueous dimethylamine was placed in a pressure reactor and heated at 110° C. for 24 hours. It was then allowed to cool and was concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution obtained was washed with 1N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain about 0.50 g of a yellow foam. This was crystallized from ethanol to obtain, after drying for 24 hours at 50° C., 0.17 g of the title compound as an off-white solid melting at 227°-228° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: c1nc[nH]n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCn1cncn1
Reaction time: 18 h
Yield: 56.8 %

Procedure:
2-Bromoethyl methyl ether (6.7 ml, 0.072 mol) was added to a stirred, ice-cooled suspension of 1,2,4-triazole (5.0 g, 0.072 mol) and potassium carbonate (10 g, 0.072 mol) in acetone (50 ml). After a further 3 hours the cooling bath was removed and stirring continued for 18 hours at room temperature. The reaction mixture was filtered, the filtrate evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using dichloromethane:methanol (95:5) as eluant, to provide the title compound (5.2 g) as a clear oil. δ (CDCl3): 3.32 (3H, s), 3.74 (2H, t), 4.34 (2H, t), 7.92 (1H, s), 8.14 (1H, s). LRMS: m/z 128 (M+1)+.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5](Br)[C:6]2[N:7]([N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:8]=1>O1CCOCC1>[Br:2][C:3]1[N:4]=[C:5]([NH2:1])[C:6]2[N:7]([N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:8]=1
Reactant: N
Reactant: Brc1cn2nc(-c3ccco3)nc2c(Br)n1
Solvent: C1COCCO1
Product: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
Anhydrous ammonia was bubbled over a one-hour period into a solution of 6,8-dibromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine (18.4 g, 0.054 mol) in dioxane (400 ml). The resulting mixture was stirred at room temperature for 2 days during which time the solution was twice recharged with ammonia by bubbling in for one hour. After concentration, diethyl ether (200 ml) was added and the resulted yellow slurry was stirred at room temperature for overnight. 6-Bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine was then collected and- dried (15 g, 99% yield). 1H NMR (300 MHz, CDCl3) δ 6.70 (dd, 1H), 7.10 (d, 1H), 7.8-8.0 (br m, 3H), 8.58 (s, 1H). MS: m/z: 280 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=1.C([CH2:18][O:19][C:20]1[C:21]([F:30])=[C:22]([C:27]([NH2:29])=[O:28])[C:23]([F:26])=[CH:24][CH:25]=1)#N>>[F:30][C:21]1[C:20]([O:19][CH2:18][C:9]2[S:10][C:6]3[CH:5]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:13]=[CH:12][C:7]=3[N:8]=2)=[CH:25][CH:24]=[C:23]([F:26])[C:22]=1[C:27]([NH2:29])=[O:28]
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(OC(F)(F)F)cc3s2)c1F
Yield: 34 %

Procedure:
Synthesised from 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide, according to Method K, scheme 26. Yield 34% (second step), mp 174-175° C., HPLC-MS (method 1): m/z 405 [M+H]+, Rt=4.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:32])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(cyclopropylcarbonyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.021 g, 0.059 mmol) and ammonium acetate (0.0452 g, 0.587 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.14 mL, 0.14 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H24ClN4O (M+H)+: m/z=359.2; Found: 359.1.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[OH:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:13]([NH:12][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1)=[S:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@H](CCO)c1ccccc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC[C@@H](NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with (R)-3-amino-3-phenylpropan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.270 g, 64%): mp 162-165° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.37 (d, J=1.8 Hz, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.07-8.01 (m, 4H), 7.63-7.61 (m, 4H), 7.35-7.34 (m, 4H), 7.25-7.26 (m, 1H), 5.58 (s, 1H), 4.65 (s, 1H), 3.39-3.40 (m, 2H), 1.90-2.03 (m, 2H); ESIMS m/z 514 ([M+H]+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cc(OC)cc(OCCCCBr)c1
Agent: Cl
Product: COc1cc(OC)cc(OCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,5-dimethoxyphenoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,5-dimethoxyphenoxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])=[CH:21][C:20]=1[Cl:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[Cl:36][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])[C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:24]
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1ccc(C(=O)NCCN2CCOCC2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CC(C)CC(C)O
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NCCN4CCOCC4)cc3Cl)nc21
Yield: 15.5 %

Procedure:
10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76; 150 mg, 0.59 mmol), 4-amino-3-chloro-N-(2-morpholin-4-ylethyl)benzamide (Intermediate 52; 168 mg, 0.59 mmol), and p-toluenesulphonic acid monohydrate (281 mg, 1.47 mmol) were heated in 4-methyl-2-pentanol (4 mL) at 140° C. for 2 hours. The reaction mixture was cooled and loaded onto an SCX-3 column pre-wet with Methanol. The column was washed with methanol to remove p-toluenesulphonic acid monohydrate and then washed with 2% 7N ammonia/methanol to elute the crude product. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as an orange gum (46 mg, 15.6%).