Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][C:20](=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
To a solution of methyl (E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-5-hydroxy-3-oxohept-6-enoate (2.85 g, 7.65 mmoles) in 12 ml anhydrous THF was added triethylborane (11.5 ml of a IM THF solution, 11.5 mmoles). The mixture was stirred for 5 minutes and cooled to -78° C. Sodium borohydride (0.333 g, 8.8 mmoles) was added followed by the dropwise addition of 5 ml methanol. The mixture was stirred for 60 minutes and quenched with the dropwise addition of aqueous H2O2 (12 ml of 30% H2O2 in 27 ml H2O). The mixture was warmed to 25° C. during 90 minutes and poured into a mixture of ethyl acetate and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 60% hexanes in ethyl acetate. The product rich fractions were concentrated in vacuo and provided 1.32 g of the oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:28])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([OH:7])=O.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:59][C@H:60]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:61]>CN(C)C=O.O>[Cl:28][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27]3)=[O:24])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([NH:59][C@H:60]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:61])=[O:7]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@H](C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
A stirred solution of 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoic acid (100 mg, 0.23 mmol) in anhydrous dimethylformamide (5 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (68 mg, 0.358 mmol), 1-hydroxy-7-azabenzotriazole (37 mg, 0.276 mmol), N,N-diisopropylethylamine (89 mg, 0.69 mmol). Ethyl alaninate (38 mg, 0.25 mmol) was added and the reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethylacetate (2×30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated to give crude product which was purified by flash silica gel column chromatography using linear gradient ethyl acetate and hexane to afford ethyl N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alaninate (43 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CN(C=O)C>[F:38][C:39]1[CH:44]=[C:43]([C:10]2[N:11]=[C:2]([NH2:1])[CH:3]=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)[CH:42]=[CH:41][CH:40]=1
Reactant: Nc1cc2cccnc2c(Br)n1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc2cccnc2c(-c2cccc(F)c2)n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-amino-8-bromo-1,7-naphthyridine (0.5 g) in a mixture of toluene (2.5 ml), DMF (4 ml) and aqueous K2CO3 (0.68 g in 2 ml water) is added bis(dibenzylideneacetone)palladium (51 mg), triphenylphosphine (47 mg) and 3-fluorphenylboronic acid (0.33 g). The mixture is stirred for 4 hours at 100° C. The mixture is diluted with ethyl acetate, then filtered through a Celite™ filter. The ethyl acetate solution is washed with 2 N NaOH and water, dried over magnesium sulphate, then concentrated to afford the title compound. MS: APCI 240.0 MH+.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[O:39][C:38]([C@H:40]([OH:42])[CH3:41])=[N:37][N:36]=3)[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:60])C(=O)C1>C(#N)C>[CH3:48][Si:47]([CH3:50])([CH3:49])[CH2:46][CH2:45][O:44][CH2:43][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:51])([CH3:1])[CH3:52])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][N:32]([C:35]3[O:39][C:38]([C@H:40]([OH:42])[CH3:41])=[N:37][N:36]=3)[CH2:33][CH2:34]2)[C:9]=1[Br:60]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](O)c1nnc(N2CCC(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4ncc(-c5ccc(-c6ccccc6)nc5)c4n3)CC2)o1
Solvent: CC#N
Product: C[C@@H](O)c1nnc(N2CCC(c3nc4c(-c5ccc(-c6ccccc6)nc5)cnn4c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c3Br)CC2)o1
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
To a solution of (R)-1-(5-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)ethanol (32 mg, 0.04 mmol) in acetonitrile (1 mL) was added NBS (7 mg, 0.04 mmol) and the resulting solution was stirred for 10 minutes and concentrated. The residue was purified on silica gel. Elution with EtOAc provided a relatively pure product (9 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([N:1]2[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]2)=[N:15][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(O)c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-n2cnc(C(=O)O)c2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid (500 mg), 6-chloropyridine-3-carbonitrile (0.93 g), and N,N-diisopropyl-ethyl-amine (3.6 mL) in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=1.73 min; Mass spectrum (APCI): m/z=215 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23]>C(O)CCCC>[CH2:8]([O:23][C:22]([C@:8]1([F:25])[C@@H:7]2[C@H:9]1[CH2:10][C@@H:11]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C@@:6]2([NH2:5])[C:26]([OH:28])=[O:27])=[O:24])[CH2:7][CH2:6][CH2:11][CH3:10]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCCCCO
Product: CCCCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Temperature: 50 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
225 μL of thionyl chloride was added to 300 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 4 mL of pentanol at ice-cooling, and the mixture was stirred for 3 hours at 50° C. After standing to cool, the reaction solution was concentrated to about 1 mL under reduced pressure, 200 mL of hexane was added thereto, and the mixture was stirred for 12 hours. After the precipitated solids were filtured, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent: water to a 50% aqueous solution of acetonitrile), thereby yielding 188 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-pentyl ester.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1>>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:51])[CH:46]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2ccc(Br)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 10, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-bromophenol, the title compound was obtained (48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.66 (br, 1H), 7.50-7.38 (m, 2H), 7.24-7.16 (m, 2H), 6.98-6.86 (m, 2H), 6.64 (d, 1H), 4.15 (br, 1H), 3.80-3.55 (m, 2H), 1.75-1.62 (m, 2H), 1.40-1.34 (m, 4H), 0.89 (t, 3H); MS (ES+) m/z 391.4 (M+1), 393.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13](Br)=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[Cu](C#N)[C:19]#[N:20]>CN(C)C(=O)C>[NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([C:19]#[N:20])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5]
Reactant: CCCCCOC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]C#N
Solvent: CC(=O)N(C)C
Product: CCCCCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 95.2 %

Procedure:
The above-described method (Example 2) was repeated to react pentyl 2-amino-5-bromo-3-methylbenzoate (2.3 g, 7.59 mmol) with copper cyanide (0.69 g, 7.74 mmol) in N,N-dimethylacetamide at 170° C. for 6 hours. Following working up similar to Example 2 and additional extraction with ethyl acetate and washing with aqueous 5% ethylenediamine solution, pentyl 2-amino-5-cyano-3-methylbenzoate (1.78 g, 89.2% of theory, 93.6 area % LC) was obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6][CH:5]=2.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)=[O:13])[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Cc1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc2[nH]1
Yield: 46 %

Procedure:
The title compound is prepared from 2-methyl-1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): tR=2.03 min; Mass spectrum (ESI+): m/z=345 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([CH3:14])([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.C(O)([C:17](F)([F:19])[F:18])=O.C(OO)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH:1]1([CH2:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:17]([F:19])[F:18])=[N:12][CH:13]=2)([CH3:14])[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(C#N)(CC1CC1)c1cncnc1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C#N)(CC1CC1)c1cnc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (2.5 g, 13.4 mmol) and DMFS (7.8 g, 26.7 mmol) in DCM (40 ml) and H2O (12 ml) at room temperature was added TFA (1.5 g, 13.4 mmol) followed by slow addition of t-BuOOH (8.6 g, 67 mmol) with vigorous stirring. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added additional DMFS (7.8 g, 26.7 mmol) and t-BuOOH (8.6 g, 67 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added aq. NaHCO3 and extracted with EtOAc (3×50 ml). The organic layer was dried over Na2SO4 and concentrated. The crude product was purification by column chromatography on silica gel (petroleum ether: EtOAc=4:1) to give 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile (1.1 g, yield: 35%). 1H NMR (CDCl3 400 MHz): δ8.97 (s, 2H), 6.82-6.55 (m, 1H), 1.92-1.90 (m, 2H), 1.85 (s, 3H), 0.71-0.65 (m, 1H), 0.60-0.57 (m, 1H), 0.51-0.47 (m, 1H), 0.26-0.20 (m, 1H), 0.03-0.00 (m, 1H).
Reaction SMILES: [C@@H:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C[Si]([Br:14])(C)C.C(N(CC)C(C)C)(C)C.C1C=C(NS(C2C=CC(N/N=C3/C=CC(C(C(O)=O)=C/3)=O)=CC=2)(=O)=O)N=CC=1>CS(C)=O>[Br:14][C@@H:4]1[C@H:5]2[CH2:6][C@H:1]([C:7](=[O:9])[O:8]2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)Br
Reactant: O=C(O)[C@H]1CC=CCC1
Agent: O=C(O)C1=C/C(=N\Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)C=CC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br

Procedure:
(R)-Cyclohex-3-enecarboxylic acid, 98.2% e.e, (2.30 g, 18.2 mmol) [Schwartz et al, J. Am. Chem. Soc., 100, 5199, (1978)] was reacted with trimethylsilyl bromide (3.01 mL, 22.8 mmol), DMSO (1.62 mL) and N,N-diisopropylethylamine (3.97 mL, 22.8 mmol) [by the method of Iwata et al, Heterocycles., 31, 987 (1990)] to give a white solid, (2.13 g, 57%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=1)[CH2:13][N:14]=[N+:15]=[N-:16].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:14]([CH2:13][C:12]2[CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=[C:10]([Br:9])[CH:11]=2)[N:15]=[N:16][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [N-]=[N+]=NCc1cc(Br)cc(C(Cl)=C(Cl)Cl)c1
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2cc(Br)cc(C(Cl)=C(Cl)Cl)c2)c1N
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.7 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (546 mg) in 20 ml of ethanol, 6.47 ml of a methanolic solution of NaOH (1N) was added and the resulting mixture was stirred at 60° C. for 20 minutes. A solution of 3-bromo-5-(trichlorovinyl)benzyl azide (1.02 g) in 10 ml of ethanol was added and the reaction mixture heated at 60° C. for two hours. The pH of the solution was adjusted to ~6 with acetic acid and then concentrated to a small volume. Dilution with 50 ml of water afforded a precipitate which was washed thoroughly with water. The precipitate was recrystallized from 8 ml of ethanol to give 466 mg of pure product, m.p. 175°-177° C..
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=3)[N:7]2[CH:8]=1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of compound 1e (600 mg, 1.92 mmol, as prepared in Step E) in 1,4-dioxane/H2O (4:1 v/v, 8 mL) was added compound 1f (560 mg, 2.44 mmol), PdCl2(dppf) (72.1 mg, 0.0960 mmol) and Cs2CO3 (847 mg, 4.99 mmol). The reaction mixture was stirred at 90° C. for 2 h under a nitrogen atmosphere. After cooling to rt, the reaction was quenched with H2O (20 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:2 v/v) to obtain compound 1g as a yellow solid (350 mg, 51% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C17H16N6O2: 337.1 (M+H). Found 337.2.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH2:20])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[S:33][C:34]([C:38](=[O:40])[CH3:39])=[C:35]([CH3:37])[N:36]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH:20][C:30]([NH:31][C:32]3[S:33][C:34]([C:38](=[O:40])[CH3:39])=[C:35]([CH3:37])[N:36]=3)=[O:29])[CH2:8]2)=[CH:21][CH:22]=1
Reactant: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Solvent: CC#N
Product: CC(=O)c1sc(NC(=O)N[C@@H]2COCC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (49 mg, 160 μmol) and (5-acetyl-4-methylthiazol-2-yl)-carbamic acid phenyl ester (49 mg, 176 μmol) were dissolved in acetonitrile (1 mL) and the mixture was stirred at room temperature. After 24 h , the mixture was concentrated, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid), then by flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide) to provide the product as a glass (18 mg, 23%). 1H NMR (300 mHz, CD3OD) δ7.05 (m, 2H), 6.87 (m, 2H), 3.90 (dd, J=11.0, 4.4 Hz, 1H), 3.84 (m, 1H), 3.53 (td, J=9.5, 4.3 Hz, 1H), 3.40 (bt, 1H), 3.10 (m, 1H), 2.90 (bd, 1H), 2.75 (bd, 1H), 2.58 (s, 3H), 2.48 (s, 3H), 2.45 (m, 3H), 2.21 (dd, J=13.6, 6.3 Hz, 1H), 1.91 (bt, 1H), 1.8-1.5 (7H), 1.37 (m, 1H), 0.92 (m, 1H), ESI MS: (M+H)+=489.4 (100%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1CCOCC1>CO>[CH2:21]([NH:29][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3ccccc3)cc2s1
Yield: 7.3 %

Procedure:
the title compound (9 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), phenethylamine (76 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 414.5 (M+1, 100%). Yield=7%.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.COC(OC)OC>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH2:1][C:3]2[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C(=O)NCCC(=O)O)cc1
Reactant: Nc1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)CCNC(=O)c1ccc(CNc2ccc(Br)cc2)cc1
Reaction time: 1 h

Procedure:
The above resin bound 3-(4-formylbenzoylamino)propionic acid (50 mg) was treated with a solution of 4-bromoaniline (500 [mol) in a mixture of DMF (500 μL) and trimethylorthoformate (500 μL). Glacial acetic acid (100 μL) was added and the mixture was shaked for 1 hour at 25° C. Sodium cyanoborohydride (750 μmol) suspended in a mixture of DMF and trimethyl-orthoformate (1:1, 1 mL) was added and the mixture was vortexed at 25° C. for 16 hours followed by filtration and washing with a mixture of DMF and water (4:1, 2×1 mL) followed by 3×1 mL DMF and 2×1 mL dichloromethane to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Br:44][C:45]1[CH:46]=[CH:47][C:48]([N:51]2[CH:55]=[C:54]([CH2:56][NH2:57])[N:53]=[CH:52]2)=[N:49][CH:50]=1>CN(C=O)C.CCOC(C)=O.O>[Br:44][C:45]1[CH:46]=[CH:47][C:48]([N:51]2[CH:55]=[C:54]([CH2:56][NH:57][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[N:53]=[CH:52]2)=[N:49][CH:50]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCc1cn(-c2ccc(Br)cn2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1cn(-c2ccc(Br)cn2)cn1)c1ccc(Cl)s1
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a solution of 5-chloro-2-thiophenecarboxylic acid (195 mg, 1.20 mmol) and triethylamine (0.400 mL, 2.87 mmol) in DMF (5 mL), BOP (550 mg, 1.24 mmol) was added. After 5 min of stirring, a solution of (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg, 1.00 mmol) in DMF (5 mL) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was purified by HPLC to give N-((1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (85 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:21]([NH:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=1)=[O:22])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2c(N)cccc2nn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2nn1

Procedure:
Prepared from 3-methylcinnolin-5-amine and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[I:14]Cl>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([F:11])([F:12])[F:13])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[I:14]
Reactant: ClI
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Solvent: ClCCl
Product: N#Cc1cc(I)c(N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 18.1 %

Procedure:
4-Amino-3-trifluoromethylbenzonitrile (100 mg, 0.54 mmol) and ICl (1.1 eq, 0.58 mmol, 96.00 mg) were added methylene chloride. The mixture was stirred for 12 hr. The reaction mixture was purified according to step 2 of Example 8 to give a title compound (30.5 mg, 18.10%).