Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:23]([O:25]CC3C=CC(OC)=CC=3)=[O:24])=[C:8](/[CH:11]=[CH:12]/[CH2:13][N+:14]([C@@H:17]([C:20](=[O:22])[NH2:21])[CH2:18][OH:19])([CH3:16])[CH3:15])[CH2:9][S:10][C@H:5]12)=[O:2].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C1(OC)C=CC=CC=1>[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40].[CH:1]([NH:3][C@@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:23]([OH:25])=[O:24])=[C:8](/[CH:11]=[CH:12]/[CH2:13][N+:14]([C@@H:17]([C:20](=[O:22])[NH2:21])[CH2:18][OH:19])([CH3:15])[CH3:16])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: COc1ccc(COC(=O)C2=C(/C=C/C[N+](C)(C)[C@H](CO)C(N)=O)CS[C@@H]3[C@H](NC=O)C(=O)N23)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[N+](C)(C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1)[C@H](CO)C(N)=O
Product: O=C([O-])C(F)(F)F

Procedure:
In a similar manner as in Example 5, the compound (4.98 g) of Example 28 was suspended in anisole (30 ml), followed by an addition of trifluoroacetic acid (33 ml) to obtain the target compound (4.03 g).
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=2)[NH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]([NH:22][C:23]([NH2:25])=[NH:24])#[N:21].[CH3:26][C:27]([CH3:29])=O>>[ClH:1].[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([N:16]3[C:27]([CH3:29])([CH3:26])[N:24]=[C:23]([NH2:25])[N:22]=[C:20]3[NH2:21])[CH:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1cccc(CCCCCC2CCCCC2)c1
Reactant: N#CNC(=N)N
Reactant: CC(C)=O
Agent: Cl
Product: CC1(C)N=C(N)N=C(N)N1c1cccc(CCCCCC2CCCCC2)c1

Procedure:
Under a nitrogen atmosphere, a solution of 2.8 grams (0.010 mole) of 3-(5-cyclohexylpentyl)aniline hydrochloride and 0.9 gram (0.011 mole) of cyanoguanidine in 100 mL of acetone was stirred at ambient temperature for about four days. After this time, the reaction mixture was filtered to collect a solid. The solid was recrystallized from methanol/diethyl ether and then from water, yielding 2.7 grams of 1-[3-(5-cyclohexylpentyl)phenyl]-2,4-diamino-6,6- dimethyl-1,6-dihydro-1,3,5-triazine hydrochloride, mp 188°-190° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][O:16][C:17]([CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:18].O>ClCCl>[CH3:15][O:16][C:17](=[O:18])[CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: Nc1cccnc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 3-aminopyridine (1 g) in dichloromethane (10 ml) was added triethylamine (1.63 ml) and 3-methoxycarbonylpropionyl chloride (1.44 ml) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with dichloromethane. The extract was washed with water, saturated aqueous NaHCO3 solution, water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1), and recrystallized from diethyl ether to give N-(3-pyridyl)succinamic acid methyl ester (0.73 g).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:20]=[CH2:21])[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[OH:22]/[N:23]=[C:24](\Cl)/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:20]3[O:22][N:23]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: C=Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C3CC(c4ccccc4)=NO3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To solution of 5-(4-isopropylsulfonylphenyl)-3-vinyl-pyrazin-2-amine (20 mg, 0.06592 mmol) in N,N-dimethylformamide (2 mL) was added (Z)—N-hydroxybenzimidoyl chloride (13.33 mg, 0.08570 mmol) followed by TEA (20.02 mg, 27.58 μL, 0.1978 mmol) added drop wise. The reaction mixture was stirred at ambient temperature for 20 mins followed by heating to 65° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and the combined organic extracts washed with water (3×10 mL), dried over MgSO4 and concentrated in vacuo to a solid. Purification by fractionlynx yielded 5-(4-(isopropylsulfonyl)phenyl)-3-(3-phenyl-4,5-dihydroisoxazol-5-yl)pyrazin-2-amine Compound I-1. (10.4 mg, 29% Yield). DMSO 1.15 (6H,d), 3.4-3.48 (1H,m) 3.7-3.8 (1H,m), 4.28 (1H,dd), 6.02 (1H,dd), 6.95 (2H,brs), 7.48-7.53 (3H,m), 7.78-7.85 (4H,m), 8.2 (2H,d), 8.75 (1H,s); LC/MS m/z 423.4 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.C1(C)C=CC=CC=1>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 76 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were put in suspension in DMSO (800 mL) under nitrogen blanket. The mixture was heated to 55° C. during 24 hours. Subsequently, toluene (200 mL) was added, the reaction mixture was cooled to 5° C., and held at this temperature overnight. The solution was filtered and dried under vacuum to obtain 43.5 g after assay (76% yield) of gatifloxacin.
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[Si:1]([C:8]1[S:9][C:10]([C:19]2([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:23][CH2:24]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1nccs1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 100 mL 3-necked round-bottom flask, was placed a solution of 2-(tert-butyldimethylsilyl)thiazole (1.58 g, 7.94 mmol, 1.00 equiv) in tetrahydrofuran (40 mL). This was followed by the addition of n-BuLi (3.7 mL, 1.20 equiv) dropwise with stirring at −78° C. in 1 hr. After half-hour, the benzyl 4-oxopiperidine-1-carboxylate (1.85 g, 7.94 mmol, 1.00 equiv) was added dropwise with stirring at −78° C. in 0.5 hr. The reaction mixture was stirred for 2 h at −78° C. in a liquid nitrogen bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate, and the combined organic layers washed with 2×100 mL of brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 2 g (58%) of benzyl 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)-4-hydroxypiperidine-1-carboxylate as yellow oil.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:15][C:13]1[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=[C:9]([NH2:8])[N:14]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cncc(C)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(Nc2ncccc2-c2nc(C)nc(N)n2)c1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-methyl-6-(2-(5-methylpyridin-3-ylamino)pyridin-3-yl)-1,3,5-triazin-2-amine (0.063 g, 0.118 mmol) in TFA (3.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature and was concentrated to about 50% of the original volume. The remaining mixture was pipetted carefully into a saturated solution of NaHCO3, which had been cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The material was suspended in DMSO (5mL) and water (10 drops) was added. The solid was collected by filtration to give 4-methyl-6-(2-(5-methylpyridin-3-ylamino)pyridin-3-yl)-1,3,5-triazin-2-amine (0.0137 g, 0.047 mmol, 39.6% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.96-12.04 (m, 1H); 8.81 (br. s., 2H); 8.39 (br. s., 1H); 8.23 (br. s., 1H); 8.05 (s, 1H); 7.89 (br. s., 1H); 7.77 (br. s., 1H); 6.96 (br. s., 1H); 2.45 (br. s., 3H); 2.32 (s, 3H). m/z (ESI, +ve ion) 294.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:16]3[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:13][C@@H:11]1[CH2:12][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](=[O:24])[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)=[C:16]3[CH:15]=2)[CH2:10]1)(=[O:54])=[O:53]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](OS(C)(=O)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-33) (150 mg, 0.26 mmol) in DCM (anhyd, 2 mL) at 0° C. was added triethylamine (0.070 mL, 0.5 mmol) followed by dropwise addition of methanesulfonyl chloride (28 μL, 0.36 mmol). After stirring 2 hours at room temperature the reaction mixture was concentrated under reduced pressure. The resulting solid was taken up in EtOAc and washed twice with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford (3R,5R)-1-(3-(bis(4-methoxybenzyl)carbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-5-(3-fluorophenyl)pyrrolidin-3-yl methanesulfonate (I-34), which was used without further purification. MS m/z 659.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24]Cl)=[N:7]1.[C-:30]#[N:31].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24][C:30]#[N:31])=[N:7]1
Reactant: COc1c2n(c3c(CCl)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c3c(CC#N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C

Procedure:
A mixture of 2-(3-chloro-4-fluorobenzyl)-4-(chloromethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.16 g, 0.37 mmol; Example 100) and sodium cyanide (30 mg, 0.61 mmol) in anhydrous DMF (2 mL) was heated in a sealed tube at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0 to 10% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:30][C:31]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Oc1nccnc1NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(piperidin-4-ylmethyl)-amino]-pyrazin-2-ol from Step 1 above (0.287 g, 1.021 mmol) in DMF (5 mL) was added triethylamine (0.356 mL, 2.55 mmol), followed by N-(benzyloxycarbonyloxy)succinimide (0.305 g, 1.23 mmol). The resulting reaction mixture was stirred at rt for 15 min, then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the crude product purified by flash column chromatography (50% EtOAc hexane to 5% MeOH EtOAc) to give an oil which solidified on standing. M.S (M+1): 343.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)ccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-bromo-2-fluoro-benzoic acid (10.0 g, 45.7 mmol) in anhydrous dichloromethane (200 mL) was added oxalyl chloride (5.2 mL, 59.4 mmol) followed by addition of anhydrous DMF (0.2 mL). The reaction mixture was stirred at room temperature overnight, then concentrated to dryness in vacuo to give title compound in quantitative yield, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[C:26]([Cl:29])(=[O:28])[CH3:27].CCN(CC)CC>C1COCC1>[ClH:29].[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:17])[F:18])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CC(=O)Cl
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(N)c2)N=C1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
A mixture of 2-amino-5-(3-amino-phenyl)-5-(4-difluoromethoxy-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one (88 mg, 0.25 mmol), acetyl chloride (20 mg, 0.25 mmol), NEt3 (51 mg, 0.51 mmol) in THF (2.5 mL) was stirred at rt for 1 h, concentrated and purified by reverse-phase HPLC followed by treatment with hydrochloric acid to provide the title compound (42 mg, 43%), characterized by NMR and mass spectral analyses. MS (ES+) m/e 389 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][NH2:10])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCBr
Product: NCC1(c2ccc(Cl)cc2)CC1
Yield: 33 %

Procedure:
(1-(4-Chlorophenyl)cyclopropyl)methylamine is prepared from 4-chlorophenyl acetonitrile and ethylene dibromide in overall 33% yield as described in Example 1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:15][CH3:16])[C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C([N+]#[C-])C1C=CC=CC=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:17][CH:1]([C:8]([O:10][CH3:11])=[O:9])[C:3]2[CH:4]=[C:5]([O:15][CH3:16])[C:6]([O:13][CH3:14])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:19][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cc(C=O)cc(OC)c1OC
Reactant: N#Cc1ccc(N)cc1
Agent: [C-]#[N+]Cc1ccccc1
Product: COC(=O)c1cc(C(Nc2ccc(C#N)cc2)C(=O)OC)cc(OC)c1OC

Procedure:
In analogy to Example 1.1, methyl 5-formyl-2,3-dimethoxy-benzoate (F. Y. Wu, D. L. b rink, J. Agric. Food Chem. (1977) 25 692) was reacted with 4-aminobenzonitrile and benzyl isonitrile to give methyl (RS)-5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2,3-dimethoxy-benzoate.
Reaction SMILES: [F:1][C:2]([F:46])([O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=1)[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:46][C:2]([F:1])([O:37][C:38]1[CH:39]=[CH:40][C:41]([S:44][CH3:45])=[CH:42][CH:43]=1)[C@@H:3]([NH:11][C@@H:12]([CH2:16][SH:17])[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CSc1ccc(OC(F)(F)[C@@H](N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c2ccc(F)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ccc(OC(F)(F)[C@@H](N[C@@H](CS)C(=O)O)c2ccc(F)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)-ethylamino]-3-tritylsulfanylpropionic acid (0.69 g, 1.04 mmol) in DCM (0.8 ml), TFA (0.322 ml, 4.18 mmol) and triethylsilane (0.332 ml) were added. After stirring 3 h, solvent and excess of TFA were evaporated under vacuum. The residue was dissolved in benzene and evaporated again on rotary evaporator to give 2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanyl-phenoxy)ethylamino]-3-mercaptopropionic acid. The residue was dissolved in 1N NaOH (4 ml) and the solution was used immediately in the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[C:15]([Cl:20])(=[O:19])[CH2:16][CH2:17][CH3:18].[OH-].[Na+]>C(O)(=O)CCC>[ClH:20].[CH3:14][C:8]1[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[C:5]=1[CH2:6][NH:7][C:2]([NH:1][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:3]2
Reactant: CCCC(=O)Cl
Reactant: CCCc1nc(C)c2n1N=C(N)NC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCCC(=O)O
Product: CCCC(=O)NC1=Nn2c(CCC)nc(C)c2CN1
Product: Cl

Procedure:
2-Amino-3,4-dihydro-5-methyl-7-propylimidazo[ 5,1-f]-as-triazine (Example 1a) (2 g.) and butyryl chloride (11 ml.) in butyric acid (50 ml.) were heated under reflux for 5.5 hours and cooled with ice. 5N sodium hydroxide was added slowly and until the mixture was alkaline and the solid was filtered off. The filtrate was evaporated under reduced pressure and the residue was stirred with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulphate, filtered and evaporated. The residue was crystallised from methanol to give a white solid, m.p. 161°-162°.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH:10]([CH2:14]I)[CH2:9]2)=[CH:3][CH:2]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9]2)=[CH:5][CH:6]=1.[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@@H:10]([CH3:14])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1N[C@H](Cc2ccc(-c3ccccc3)cc2)CC1CI
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one (12-a, R1=H, R5=I) is added to ethanol (1 ml) at ambient temperature. Triethylamine (5 μl) is then added to the mixture. 0.4 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (3-a, R1=H) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (3-b, R1=H. Ratio of diastereomers 22:88 (3-a, R1=H to 3-b, R1=H) as determined by nmr. Spectroscopic data for 3-a (R1=H) as for Example 6 in WO/2008/083967. Spectroscopic data for 3-b (R1=H) as for Example 47 in WO/2008/083967.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19]Br)=[CH:4][CH:3]=1.[NH3:21].CO>O1CCCC1>[NH2:21][CH2:19][C:5]1[C:6]([F:18])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reaction time: 16 h
Yield: 21 %

Procedure:
A solution of 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (2.5 g, 5.96 mmol) in tetrahydrofuran (THF) (50 mL) was added dropwise to a 7M solution of ammonia in MeOH (42.6 mL, 298 mmol) at RT under nitrogen. The reaction was stirred for 16 h then the reaction mixture was evaporated to dryness. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue and the mixture was shaken in a separatory funnel. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography with hexane:ethyl acetate to give the title compound (0.453 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (s, 1H), 7.56 (d, 1H), 7.39-7.46 (m, 2H), 7.37 (m, 1H), 3.70 (s, 2H), 1.85 (br. s., 2H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:11]=[C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[O:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:21]([CH:23]1[O:25][CH2:24]1)Br>>[C:3]([C:7]1[CH:11]=[C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:23]2[O:25][CH2:24]2)[O:9][N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2O)on1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This is prepared, using the method described in Example VI, from 3.8 g of 55% strength sodium hydride (0.086 mole), 21 g (0.086 mole) of 3-tert.-butyl-5-(2-hydroxystyryl)-isoxazole and 11.8 g (0.086 mole) of epibromohydrin. 25.0 g (97% of theory) of a colorless oil are obtained.