Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:43]=2[S:44][C:45]=1[C:46](Cl)=[O:47]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:46]([C:45]2[S:44][C:43]3[CH:49]=[CH:50][CH:51]=[C:52]([F:53])[C:42]=3[C:41]=2[Cl:40])=[O:47])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
N3 is prepared according to a method similar to Method D. [4-(2-methoxy-5-pyridin-3-yl-benzylamino)-cyclohexyl]-carbamic acid tert-butyl ester (N2) (1.035 g, 2.52 mmol) is dissolved in 10 mL anhydrous methylene chloride. N,N-Diisopropylethylamine (0.526 mL, 3.02 mmol) is added followed by 3-chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride (6) (0.690 g, 2.77 mmol). The mixture is allowed to stir overnight at room temperature and then is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and evaporated, and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. {4-[(3-Chloro-4-fluoro-benzo[b]thiophene-2-carbonyl)-(2-methoxy-5-pyridin-3-yl-benzyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (N3) is obtained (0.93 g, 1.48 mmol; 59% yield).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22]CC2C=CC=CC=2)[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5]>[Pd].C(O)C>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:2][F:1]
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(CF)CF)c2)n1
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (2.46 g, 6.13 mmol) and 10% by weight palladium on carbon (0.246 g) in ethanol (100 mL) was allowed to stir at RT, under a hydrogen atmosphere overnight. The solution was filtered through Celite® and the cake washed with methanol (100 mL). The solution was evaporated to give the desired compound (1.78 g). 1H NMR δ (d6-DMSO): 3.78 (s, 3H), 4.72 (m, 4H), 4.97 (m, 1H), 6.57 (d, 2H), 7.03 (s, 1H), 7.16 (s, 1H), 7.59 (s, 1H). m/z 312 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][O-:14].[Na+].[NH2:16][NH2:17]>COCCO>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:4][N:3]=1)[NH2:17]
Reactant: COCC[O-]
Reactant: ClCc1ccc(Cl)nc1
Reactant: NN
Agent: [Na+]
Solvent: COCCO
Product: COCCOCc1ccc(NN)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1620 mg, 10 mmol) in 2-methoxyethanol (10 mL) was added sodium 2-methoxyethanolate (5.9 g, 12.00 mmol). The mixture was stirred at room temperature for 10 min and then at 50° C. for 2 hrs. Hydrazine (1.6 g, 50.0 mmol) was then added to the mixture and the reaction was heated at 120° C. for 1 hr. The mixture was purified by preparative LCMS to provide the title compound, 2-hydrazinyl-5-((2-methoxyethoxy)methyl)pyridine (540 mg, 27.4% yield).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C)C=O.Cl.[CH2:13]([N:16]([CH:20]=[C:21]1[CH:29]=[CH:28]C(C(O)=O)=[CH:23][CH2:22]1)[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>ClCCl>[CH2:17]([N:16]([CH:20]=[C:21]1[CH:22]=[CH:23][C:1]([C:2]([Cl:4])=[O:3])=[CH:28][CH2:29]1)[CH2:13][CH2:14][CH3:15])[CH2:18][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCN(C=C1C=CC(C(=O)O)=CC1)CCC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C=C1C=CC(C(=O)Cl)=CC1)CCC

Procedure:
0.283 cm3 of oxalyl chloride and then a drop of dimethylformamide are successively added, at a temperature close to 20° C., to a suspension of 0.748 g of 4-(N,N-di-n-propylaminomethylene)benzoic acid monohydrochloride in 20 cm3 of dichloromethane. The reaction medium is kept stirred at a temperature close to 20° C. until the gaseous emission ceases, and then concentrated to dryness under reduced pressure (about 0.5 kPa) at a temperature close to 35° C. The white solid thus obtained is used as a base for the preparation of 4,4′-O,O-di(4-(N,N-di-n-propylaminomethylene)benzoyl)-2-[(1R,2S,3R)(1,2,3,4-tetrahydroxybutyl)]-5-[(2′S, 3′R)(2′,3′,4′-trihydroxybutyl)]pyrazine.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][CH2:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:21][CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:28])=[O:24]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)CNC(=O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)CNC(=O)CCl)C(=O)OCC
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a suspension of diethyl 2-aminomalonate hydrochloride (4.2 g) in tetrahydrofuran are added triethylamine (2.1 g) and N-(chloroacetyl)glycine (3.0 g), and the mixture is cooled to 0° to 5° C. To the mixture is further added N,N'-dicyclohexylcarbodiimide (4.3 g), and the mixture is stirred at the same temperature for 2 hours and then allowed to stand at room temperature overnight. Insoluble substance is filtered off from the reaction mixture, and the filtrate is concentrated under reduced pressure. To the residue is added ethyl acetate, and the insoluble substance is filtered off. The filtrate is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetateisopropyl ether to give diethyl 2-[[N-(chloroacetyl)glycyl]amino]malonate (5.1 g), m.p. 104.5°-105° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)(=O)=O.[CH2:29]([NH2:31])[CH3:30]>C1COCC1>[CH2:29]([NH:31][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH3:30]
Reactant: CCN
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)OCC)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ethyl(4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25-1.45 (3H, m), 1.55-1.65 (2H, m), 1.70-1.80 (1H, m), 2.05-2.15 (1H, m), 3.25-3.35 (2H, m), 3.79 (1H, t), 3.90-3.95 (2H, m), 4.10-4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP-HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4](N)[CH:5](C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.C([N:38]([CH:41](C)C)CC)(C)C.FC(S(OC[P:53]([O:57][CH3:58])([O:55][CH3:56])=[O:54])(=O)=O)(F)F>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]([NH:38][CH2:41][P:53]([O:57][CH3:58])([O:55][CH3:56])=[O:54])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)C(Cc1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: COP(=O)(COS(=O)(=O)C(F)(F)F)OC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(S)-3-t-Butoxycarbonyl-amino-4-(biphenyl-4-yl)-butyric acid methyl ester (716 mg, 2 mmol) is stirred for 1 hour in a 1/l mixture of trifluoroacetic acid and methylene chloride (5 mL). Ethyl acetate (20 mL) is added and the solution is washed with saturated sodium bicarbonate (20 mL). The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in methylene chloride (10 mL) and cooled to 0° under nitrogen. Diisopropyl ethylamine (0.42 mL, 2.4 mmol) is added, followed by a solution of dimethylphosphonomethyl trifluoromethylsulfonate (Tetrahedron Lett., 1986, 1477; 545 mg, 2.2 mmol). The mixture is stirred for 18 hours at room temperature. The solution is washed with saturated sodium bicarbonate, water and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash-chromatography to afford (S)-4-(biphenyl-4-yl)-3-[(dimethylphosphonomethyl)-amino]-butyric acid methyl ester as a white solid, m.p. 67°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=1.ClC1C=C(Cl)C=CC=1C1[C:35]([C:36]2[NH:37][CH:38]=[CH:39][N:40]=2)=[CH:34][N:33]=[C:32]([NH:41][CH2:42][CH2:43][NH:44]C2C=CC([N+]([O-])=O)=CN=2)[N:31]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:35]([C:36]3[NH:37][CH:38]=[CH:39][N:40]=3)=[CH:34][N:33]=[C:32]([NH:41][CH2:42][CH2:43][NH:44][C:14]3[N:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=3)[N:31]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: COc1cc(Cl)ccc1-c1nc(NCCNc2ccc(C#N)cn2)ncc1-c1ncc[nH]1

Procedure:
6-[(2-{[4-(4-chloro-2-methoxyphenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}-ethyl)amino]pyridine-3-carbonitrile was prepared from 4-chloro-2-methoxybenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[C:47]3[C:43]([CH2:44][CH2:45][C:46]3=[O:49])=[CH:42][CH:41]=2)O1>COCCOC.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>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:48]=[C:47]3[C:43](=[CH:42][CH:41]=2)[CH2:44][CH2:45][C:46]3=[O:49])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)CC3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)C(=O)CC2
Yield: 56.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.059 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and intermediate 18 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (0.325 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.117 g (56%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1cccc(S)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.8 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.0 mmol of 3-methoxybenzenethiol, and 2.0 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 61°-62° C.). 1H NMR (DMSO-d6) δ 3.63 (s, 3 H), 3.76 (s, 2 H), 5.64 (bd, 1 H), 6,42 (s, 1 H), 6.54 (d, 1 H), 6.74 (t, 1 H), 7.32-7.47 (m, 10 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[Li+].[F:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:25])[CH:3]=2)[N:10]=1
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ccncc4F)c3)n2)c(F)c1
Temperature: 80 °C
Yield: 42.2 %

Procedure:
A mixture of 5-(3-bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (from Example 8 below) (120 mg, 0.33 mmol), lithium chloride (70 mg), cuprous iodide (6.3 mg) and 3-fluoro-4-tributylstannylpyridine (120 mg, 0.31 mmol) in dry 1,4-dioxane (5 ml) was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (30 mg) was added and the mixture heated under an atmosphere of nitrogen at 80° C. for 48 h. On cooling to room temperature the mixture was partitioned between dichloromethane (30 ml) and 25% aqueous ammonium hydroxide (15 ml). The organic layer was separated, solvent removed at reduced pressure, and the residue subjected to preparative thin layer chromatography on silica gel, eluent 2% methanol in dichloromethane. The product was recrystallised from hot toluene to give 3-(2,4-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-[1,2,4]triazine as a solid (50 mg): δH (500 MHz, d6-DMSO) 7.35 (1H, m), 7.52 (1H, m), 7.73 (2H, m), 8.34 (1H, m), 8.63 (3H, m), 8.78 (1H, s), 10.18 (1H, s); m/z (ES+) 383.
Reaction SMILES: Cl.Cl.Cl.[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([C:20]4[N:21]=[C:22]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[N:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=45)=[CH:15][CH:16]=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(N(CC)CC)C.CN(C=O)C>[NH2:29][C:25]1[C:24]2[N:23]([C:22]([CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)=[N:21][C:20]=2[C:14]2[CH:13]=[C:12]3[C:17]([CH:18]=[CH:19][C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[N:11]3)=[CH:16][CH:15]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 1 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine-tris HCl salt (59.0 mg, 0.1 mmol) was dissolved in triethylamine (1.0 mL) and DMF (0.5 mL). Acetic anhydride (12.0 μL, 0.1 mmol) was added and the reaction was stirred for 1 h. The reaction was concentrated in vacuo and purified by silica gel chromatography (Jones Flashmaster, 2 g/12 mL cartridge, eluting with 2% 7N NH3 in methanol/CH2Cl2). The sample was further purified using MDPS to yield 1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.95 (ddd, 1H, J=22.4, 11.2, 4.0 Hz), 2.03-2.23 (m, 6H), 2.90 (ddd, 1H, J=13.6, 13.6, 2.8 Hz), 3.19-3.32 (m, 2H), 4.01 (bd, 1H, J=13.6 Hz), 4.64 (bd, 1H, J=13.2 Hz), 5.44 (bs, 2H), 7.11 (d, 1H, J=4.8 Hz), 7.24 (d, 1H, J=5.6Hz), 7.46 (ddd, 1H, J=6.0, 2.4, 0.8 Hz), 7.50-7.54 (m, 2H), 7.86-7.94 (m, 3H), 8.16 (ddd, 2H, J=7.2, 3.6, 1.6 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.38 (s, 1H); MS (ES+): m/z 463 (10) [MH+]; HPLC: tR=2.1 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[F:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cc(F)cc(Br)c1
Product: Fc1cc(F)cc(-c2ccccc2)c1
Yield: 91.1 %

Procedure:
Combine 1-bromo-3,5-difluorobenzene (0.863 mL, 7.50 mmol) and phenylboronic acid (1.22 g, 10.00 mmol) and subject to conditions described in Method G to yield 1.3 g of 3,5-difluorobiphenyl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](NC)=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1.C(N)(=O)C1C=CC=CC=1.[CH3:47][O:48][CH2:49][CH2:50][OH:51]>>[CH3:47][O:48][CH2:49][CH2:50][O:51][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([Cl:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)[N:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Reactant: COCCO
Agent: NC(=O)c1ccccc1
Product: COCCOC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)O)CC3)ncc1Cl

Procedure:
In an analogous manner to Example 1534, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. The 2-methoxyethanol solvent reacted with the benzamide resulting in the product (28 mg, 25%). mp: 100° C., MS (ESI+): 556 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.86 (d, J=8.6 Hz, 1H), 8.17 (s, 2H), 8.15 (s, 1H), 7.53 (t, J=8.1 Hz, 1H), 7.49 (s, 2H), 7.11 (t, J=7.2 Hz, 1H), 6.68 (s, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.90 (s, 4H), 3.79 (t, 2H), 3.46 (m, 2H), 2.96-2.82 (m, 6H), 2.62 (m, 2H), 2.61 (d, J=110 Hz, 1H), 2.27 (t, J=9 Hz, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18](=[O:21])[NH:19][NH2:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:20][NH:19][C:18]([O:17][CH3:16])=[O:21])[C:7]=2[CH:15]=1)#[N:2]
Reactant: COC(=O)NN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: COC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A similar procedure to Reference Example 5 was performed by using 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and methylcarbazate, and as a result, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-methoxycarbonylhydrazino)-2H-1-benzopyran-3-ol was obtained, m.p. 174°-175° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [O-:1]C#N.[Na+].[NH2:5][C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.O>[Br:16][C:14]1[CH:13]=[CH:12][C:7]2[C:8](=[O:9])[O:10][C:11](=[O:1])[NH:5][C:6]=2[CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
87.0 g (1.33 mol) of sodium cyanate were added to 269.0 g (1.17 mol) of methyl 2-amino-4-bromobenzoate in 1.2 l of acetic acid with stirring at room temperature, and the mixture was subsequently stirred for a further 22 h. The reaction mixture was diluted with 1.5 l of water, and the residue was filtered off with suction. 0.42 l of sodium hydroxide solution (32%) was added to the solid, the mixture was diluted with 3.5 l of water and heated on a steam bath for 4 h. After cooling, the solid residue was filtered off with suction. Conventional work-up gave 205.2 g of 7-bromo-1H-benzo[d]-1,3-oxazine-2,4-dione; HPLC/MS (M+H)+=243 as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:19][C:20]1[C:21]([OH:31])=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[C:21]([OH:31])=[C:22]([S:27]([NH:17][CH2:16][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])([OH:18])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1cc(Cl)cc(Cl)c1O

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 3,5-dichloro-2-hydroxybenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH:44]1[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:44]1[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-L-proline (2 g, 9.3 mmol), EDAC (3.5 g, 18 mmol), HOBt (1.35 g, 10 mmol) in DMF (20 mL) was added triethylamine (2 mL, 14 mmol) and (R)-(+)-3-pyrrolidinol (1.5 mL, 18 mmol). After stirring at room temperature for 48 h, the reaction was quenched with water and sodium bicarbonate solution. It was then extracted with 5% of methanol in dichloromethane. The residue was purified on a silica gel column eluting with 10% of methanol in dichloromethane to give 2.2 g (83%) of (S)-2-((R)-3-hydroxy-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.