Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:51]([O:53][C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O)=[O:55])[CH3:52].CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:51]([O:53][C:54](=[O:55])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:18]1[C:17]2[CH2:33][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:35](=[O:36])[C:16]=2[C:15]([O:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2)[CH3:52]
Reactant: CCOC(=O)c1ccccc1B(O)O
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 120 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (33.5 mg, 0.05 mmol) dissolved in toluene (3 mL)/ethanol (0.6 mL)/water (0.4 mL) was added K2CO3 (22 mg, 0.15 mmol), (2-ethoxycarbonylphenyl)boronic acid (22 mg, 0.10 mmol) and tetrakis-(triphenylphosphine)-palladium(0)(12.5 mg, 0.01 mmol). The reaction mixture in the flask was flashed with argon three times. It was then heated to 120° C. under argon 3 hours. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 46=0.6, Rf 281=0.5) and LC/MS. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with EtOAc/Hexane (3/7) to afford pure 2-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoic acid ethyl ester 281, 9 mg, 26.8%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[C:38]2[CH2:37][CH2:36][N:35]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:34][CH2:33][C:32]=2[CH:31]=[CH:30][C:29]=1[Cl:45]>C(Cl)Cl.O>[Cl:45][C:29]1[CH:30]=[CH:31][C:32]2[CH2:33][CH2:34][N:35]([C:39](=[O:44])[C:40]([F:42])([F:41])[F:43])[CH2:36][CH2:37][C:38]=2[C:28]=1[O:27][CH2:26][CH2:25][NH:24][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C(O)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
Combine picolinic acid (40 mg, 0.327 mmol), EDC (57 mg, 0.297 mmol) and HOBT (40 mg, 0.297 mmol) in DCM (3 mL). Stir for 10 min at ambient temperature. Add 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.297 mmol). Stir for 16 h at ambient temperature. Dilute with DCM, add water and extract the aqueous layer with DCM. Wash the combined organic extracts with 1M aqueous NaOH and brine. Dry the organic layer over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (3:2) to give 7-chloro-6-{2-[(pyridine-2-carbonyl)-amino]-ethoxy}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (94 mg, 74%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH3:10].Br[CH2:24][CH:25]([CH3:27])[CH3:26]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:22])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:10]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (4.88 mL of 0.29 M stock solution, 1.41 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid ethyl ester (300 mg, 1.28 mmol) in tetrahydrofuran/hexamethylphosphoramide (3.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 1-bromo-2-methyl-propane (1.53 mL, 1.41 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 6 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (1 mL). This mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-4-methyl-pentanoic acid ethyl ester (356.4 mg, 95.8%) as a clear oil: EI-HRMS m/e calcd for C14H18Cl2O2 (M+) 288.0683, found 288.0677.
Reaction SMILES: Cl[C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][OH:23]>>[C:14]([O:13][C:11]([N:7]1[CH2:8][C@@H:9]([CH3:10])[N:4]([C:2]([O:23][CH2:22][C:21]2[C:20]([F:19])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])=[O:3])[C@@H:5]([CH3:18])[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: OCc1c(F)cccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)OCc1c(F)cccc1F

Procedure:
2,6-Difluorobenzyl 4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,6-difluorobenzyl alcohol according to the method described for Example 54 to give the product as a colourless gum (0.251 g, 65%); Rf (Silica, isopropyl ether) 0.35; δH (400 MHz, CDCl3) 7.29 (1H, m), 6.90 (2H, m), 5.23 (2H, s), 4.16 (2H, m), 3.92 (2H, br), 2.95 (2H, br), 1.47 (9H, s), 1.21 (6H, d, J 6.8 Hz).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:34]1([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH:34]1([CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[S:24][CH2:23][CH2:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:21])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: NCC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
264 mg (1.62 mmol) of CDI were added to a solution of 500 mg (1.55 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (12 ml), and the mixture was stirred for 1 h at RT. A solution of 200 μl (1.55 mmol) of cyclohexanemethylamine in DCM (12 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 624 mg (1.49 mmol, 96%) of N-(cyclohexylmethyl)-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COc1ccccc1OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: COc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.786 g of 1-(3-bromopropoxy)-2-methoxybenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=4.91.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][CH:15]([CH3:26])[N:14]([C:27](=[O:30])[NH:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1>ClCCl>[CH3:29][NH:28][C:27]([N:14]1[CH:15]([CH3:26])[CH2:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:20]3=[CH:19][C:18]=2[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=2)=[N:13]1)=[O:30]
Reactant: CN=C=O
Reactant: CNC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(C2=NN(C(=O)NC)C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 79 %

Procedure:
After adding 0.5 ml (8.5 mmol) of methyl isocyanate to 0.6 g (1.7 mmol) of 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 98) dissolved in 45 ml of anhydrous dichloromethane, the reaction mixture was stirred at 25° C. for 6 days. Then the crystalline precipitate was filtered, washed with 3×2 ml of dichloromethane and dried at 60° to 80° C. to obtain 0.55 g (79.7%) of the pure aimed product, m.p.: 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][O:19][C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].[OH-].[Na+].Cl>>[C:21]([CH2:20][CH:17]1[C:16]2[C:11]([C:9]([NH:8][C:7]3[C:6]([Cl:28])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[O:10])=[CH:12][CH:13]=[C:14]([O:26][CH3:27])[C:15]=2[O:19][CH2:18]1)([OH:23])=[O:22]
Reactant: CCOC(=O)CC1COc2c(OC)ccc(C(=O)Nc3c(Cl)cncc3Cl)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Compound 5 (0.329 g) obtained in Example 5 was mixed with a 2N aqueous solution of sodium hydroxide (6.6 ml), followed by stirring at room temperature for one hour. Under ice-cooling, the reaction mixture was adjusted to pH 2 by adding hydrochloric acid, and then the precipitated solid was collected by filtration. The obtained crude product was recrystallized from ethanol to give Compound 9 (0.302 g, 98%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([N:12]=[C:13]=S)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1C=CC=CC=1>[Br:1][C:2]1[C:11]([NH:12][C:13]2[NH:17][CH2:16][CH2:15][N:18]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: S=C=Nc1ccc2nccnc2c1Br
Reactant: NCCN
Solvent: c1ccccc1
Product: Brc1c(NC2=NCCN2)ccc2nccnc12
Reaction time: 2 h

Procedure:
The 5-bromo-6-isothiocyanato-quinoxaline (3.5 g.) is directly dissolved in benzene (400 ml) and added dropwise to a well-stirred solution of ethylene diamine (15 g.) in benzene (50 ml). During a period of about two hours, an oil separates as a lower layer. The upper benzene layer is poured off and the oil is washed with diethyl ether and then dissolved in methanol (500 ml). The methanolic solution is refluxed until hydrogen sulfide evolution ceases. The methanolic solution is concentrated in vacuo to a volume of approximately 100 ml upon which a yellow solid precipitates. The precipitate is collected by filtration and recrystallized from methanol to afford of (5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine: m.p. 250-251 C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52]C(C(C)(C)C)(C)O[SiH3])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=[O:63])C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:63])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CC(C)(O[SiH3])C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 409.1 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]tert-butyl-dimethyl-methoxy]silane 3h (4.7 g, 5.46 mmol) was dissolved in 50 mL methanol, followed by addition of acetyl chloride (80 mg, 0.82 mmol). The reaction mixture was stirred for 1 hour at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydro-pyran-2-yl]methanol 31 (2.5 g, yellow grease), yield: 61.4%.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)(OCC)=[O:2].[CH:16]1[C:17](/[CH:32]=[N:33]/[OH:34])=[CH:18][CH:19]=[N+:20]([CH2:22][N+:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[N:30]/[OH:31])=[CH:25][CH:24]=2)[CH:21]=1.[Br-:35].[Br-].[H-].C([Al+]CC(C)C)C(C)C.[K+].[Br-]>>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1.[CH:18]1[C:17](/[CH:32]=[N:33]/[OH:34])=[CH:16][CH:21]=[N+:20]([CH2:22][N+:23]2[CH:24]=[CH:25][C:26](/[CH:29]=[N:30]/[OH:31])=[CH:27][CH:28]=2)[CH:19]=1.[Br-:35].[Br-:35]
Reactant: CCOC(=O)CCCCC1=CCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Product: O=C1CCC=C1CCCCCO

Procedure:
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050, 886 cm-1. λmaxMeOH 243 (12,020).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH2:31][C:32]([OH:34])=[O:33])[CH:9]=[CH:10][C:11]=1[NH:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:5])[CH3:2].[CH2:35]([O:37][C:38](=[O:53])[C:39]([CH2:51]O)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH3:36]>>[CH2:43]([O:42][C:40](=[O:41])[C:39]([CH2:51][O:33][C:32](=[O:34])[CH2:31][C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][CH:22]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:38]([O:37][CH2:35][CH3:36])=[O:53])[CH3:44]
Reactant: CCOC(=O)c1cc(CC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Product: CCOC(=O)c1cc(CC(=O)OCC(C(=O)OCC)(C(=O)OCC)c2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 64.5 %

Procedure:
The 3-ethoxycarbonyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acid (0.532 g) obtained in Example 9-4e) and the 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (1.04 g) obtained in Example 1-2a) were treated in a similar manner to Example 1g) to give the title compound (0.524 g) (see Table 59).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[OH-].[Na+].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[C:4]([CH2:3][NH:2][S:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])=[O:15])#[N:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCNS(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 27.8 g (0.3 moles) aminoacetonitrile hydrochloride and 24.0 g (0.3 moles) 50% aqueous sodium hydroxide in 200 ml water, 17.7 g (0.1 mole) benzenesulfonyl chloride were dropped in over about 25 minutes. During the addition, the temperatures of the reaction mixture was kept under 20° C. using an ice bath. After the addition was complete, the ice bath was removed; stirring of the reaction mixture continued for about 30 minutes. The solids which formed were isolated by filtration and were washed with 200 ml water. The resulting beige solids were dissolved in 150 ml methylene chloride, dried over magnesium sulfate and stripped. The resulting white solids were washed with hexane, filtered and air-dried to give 13.9 g of the above-identified product, melting point 81°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:16][N:15]=[N:14][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a solution of 4-cyanomethyl benzoic acid methyl ester (2.63 g, 15 mmol) in anhydrous toluene (100 mL) was added sodium azide (1.95 g, 30 mmol) and triethylamine hydrochloride (4.13 g, 30 mmol). The reaction mixture was stirred at 100° C. for 24 hours under nitrogen. The reaction mixture was cooled to room temperature, then extracted with water (2×100 mL). The aqueous layer was acidified with concentrated HCl to pH approximately 4. The white solid was filtered off, washed with water, and dried under vacuum at 40° C. overnight, to give methyl-4-(1H-tetrazol-5-ylmethyl)benzoate (2.88 g, 88%) as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].CON(C)[C:15]([C:17]1[S:24][C:23]([CH3:25])=[C:22]2[C:18]=1[CH2:19][C@H:20]1[C:26]([CH3:28])([CH3:27])[C@H:21]12)=[O:16]>C1COCC1>[CH3:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][C:15]([C:17]1[S:24][C:23]([CH3:25])=[C:22]2[C:18]=1[CH2:19][C@H:20]1[C:26]([CH3:28])([CH3:27])[C@H:21]12)=[O:16]
Reactant: CON(C)C(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: COc1ccccc1CCBr
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
At rt, a solution of 1-(2-bromo-ethyl)-2-methoxy-benzene (1.0 g, 4.15 mmol) in abs. THF (5 mL) is added to Mg turnings (0.13 g, 5.35 mmol) suspended in abs. THF (5 mL) over a period of 20 min. The thus obtained Grignard reagent is then added at to an ice-cold solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (400 mg, 1.5 mmol) in THF (5 mL). The reaction mixture is stirred at rt for 1 h, quenched by adding sat. aq. NH4Cl (10 mL), diluted with water (100 mL) and extracted twice with DCM (100 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The resulting residue is purified by prep. HPLC to afford 3-(2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta-len-4-yl)-propan-1-one (390 mg) as a colourless oil. LC-MS: tR=1.15 min, [M+1]+=341.21; 1H NMR (CDCl3): δ 7.22-7.14 (m, 2H), 6.90-6.81 (m, 2H), 3.82 (s, 3H), 3.20-2.90 (m, 5H), 2.79 (d, J=18.8 Hz, 1H), 2.38 (s, 3H), 1.88 (d, J=2.9 Hz, 2H), 1.12 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21])=[N+]=[N-].[H][H]>CO>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: [H][H]
Solvent: CO
Product: NC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Yield: 91 %

Procedure:
The thus-obtained 5′-azido-5′-deoxyinosine was then dissolved in methanol and reduced with hydrogen for 12 hours using palladium-on-carbon Pd/C (10%, 80 mg) as a catalyst, whereby 5′-amino-5′-deoxyinosine was obtained. Yield 91%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)cc(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol) and 3,5-dimethoxyaniline (35 mg, 0.23 mmol), similar to Example 180 and was isolated as a pale solid (30 mg, 52%). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 7.78 (m, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 6.53 (d, J=2.1 Hz, 2H) 6.39 (t, J=2.1 Hz, 1H), 3.83 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccccc4F)C3)nc(N)n2)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccccc3F)C2)n1
Temperature: 150 °C
Yield: 10.2 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(2-fluorophenyl)-3-piperidinecarboxamide (191 mg, 0.440 mmol), 3 mL of EtOH, Hunig's base (0.077 mL, 0.440 mmol), and hydrazine anhydrous (0.055 mL, 1.759 mmol) were added, and the resulting yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 1H), 1.84 (m, 2H), 2.01-2.20 (m, 1H), 3.21-3.24 (m, 2H), 3.44-3.61 (m, 1H), 4.36-4.53 (m, 1H), 4.61-5.09 (m, 1H), 6.97 (m, 1H), 7.17 (m, 3H), 7.39 (s, 1H), 7.67-8.01 (m, 3H), 9.84 (m, 1H), 11.87-12.17 (m, 2H).