Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:15])[C:3]=1[F:16]>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:15])[C:3]=1[F:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c(F)c1F

Procedure:
Prepared analogously to example 1b by hydrogenation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate using palladium/charcoal 10% in methanol and dichloromethane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:24](OCC)(=[O:26])C>COCCOC.[Pd]>[C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:24](=[O:26])[N:11]3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1
Agent: [Pd]
Solvent: COCCOC
Product: O=C1Nc2ccccc2N2CCN(Cc3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-(phenylmethyl)-1H-1,2,5-triazepine (10.0 g) in 1,2-dimethoxyethane (250 ml) was hydrogenated at over 10% palladium on carbon (2.5 g) at room temperature and atmospheric pressure until theoretical uptake had been achieved. At this stage the reaction solution was colorless and t.l.c. on Alox-25 uv254 plates (Brinkmann) with ethyl acetate as developer showed a single component. The mixture was filtered through Celite and the filter pad washed with 1,2-dimethyloxyethane. The filtrate was evaporated to approximately 150 ml and 1,1-carbonyldiimidazole (20 g) was added. The solution was evaporated to dryness and the residue was dissolved in chloroform and applied to a column (75×6.4 cm) of dry column grade neutral alumina prepacked in chloroform. Elution with chloroform removed a major component from the column. Fractions were monitored by t.l.c. on Alox-25 un254 plates with ethyl acetate as developer. Appropriate fractions were evaporated and the crude titled product was crystallized from chloroform-heptane (seeding); wt. 7.56 g (77%), mp=129°-131°. Two crystallizations from the same solvent gave pure product, mp=127°-128°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[NH:8][C@@H:7]1[C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])=[O:5])[CH3:2].[CH:23]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([O:3][C:4]([C@H:6]1[NH:8][C@@H:7]1[C:9]([NH:11][C@H:12]([C:20]([NH:30][CH2:29][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])=[O:5])[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)[C@H]1N[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CCOC(=O)[C@H]1N[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC1CCCCC1

Procedure:
In substantially the same manner as Working Example 26, Compound 26b (1.22 g) was condensed with cyclohexanemethylamine (0.50 g, manufactured by Wako Pure Chemical Industries, Ltd.) to give the above-titled compound. (Compound 87; 0.85 g) as white crystals (yield 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22](Br)[CH:21]=1>COCCOC>[Br:19][C:20]1[CH:21]=[C:22]([C:5]2[C:6]([C:7]#[N:8])=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Fc1cc(Br)cc(Br)c1
Solvent: COCCOC
Product: N#Cc1cc(F)ccc1-c1cc(F)cc(Br)c1
Temperature: 65 °C
Yield: 9.4 %

Procedure:
5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.99 g, 4.0 mmol) and 1,3-dibromo-5-fluorobenzene (1.52 g, 6.0 mmol) were suspended in 1,2-dimethoxyethane (8 ml) and 2N sodium carbonate solution (4 ml) and degassed for 30 min before addition of tetrakis(triphenylphosphine)palladium(0). On complete addition the mixture was heated at 65° C. for 20 h. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml), the organic layer separated and washed with brine (50 ml), dried over anhydrous sodium sulphate, filtered and evaporated onto silica. The product was purified by flash column chromatography on silica, eluting with isohexane on a gradient of diethyl ether (5-100%). Combination of the desired fractions and evaporation gave 3′-bromo-4,5′-difluorobiphenyl-2-carbonitrile (110 mg, 9%) as a white solid: δH (500 Mfz, CDCl3) 7.53-7.55 (1H, m), 7.67 (1H, s), 7.69-7.76 (3H, m), 8.03 (1H, dd, J 9 and 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH:23][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[S:21][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(Cl)c2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(Cl)c2)cc1
Yield: 47315.8 %

Procedure:
Compound 3 was synthesized from the reaction of 3-4 (70 mg, 0.19 mmol) with DMAP (46 mg, 0.38 mmol) and isonicotinoyl chloride hydrochloride (44 mg, 0.25 mmol). The reaction provided compound 3 (42 mg, 89.9 mmol) in 47% yield: 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J=6.0 Hz, 2 H), 7.70 (d, J=6.0 Hz, 2 H), 7.46 (d, J=8.8 Hz, 2 H), 6.96 (d, J=8.8 Hz, 2 H), 6.92 (s, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 3.86 (s, 3 H), 2.01 (s, 3 H); ESI-MS: m/z 466.1 (M−H)−.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][CH3:14])[CH2:7][CH2:6]1)=[O:4].[C:36]([OH:45])(=[O:44])[CH:37]([CH:39]([C:41]([OH:43])=[O:42])[OH:40])[OH:38]>C(OCC)(=O)C>[OH:40][C@H:39]([C@@H:37]([OH:38])[C:36]([OH:45])=[O:44])[C:41]([OH:43])=[O:42].[OH:1][NH:2][C:3]([C:5]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][O:13][CH3:14])[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COCCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)CC1
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added tartaric acid (48 mg, 0.3 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.2 g, 58.3%). Analytical calculation for C22H25N2O7SF3.0.5C4H6O6.1.25H2O: C, 46.79; H, 4.99; N, 4.55; S, 5.20. Found: C, 47.17; H, 5.20; N, 4.07; S, 5.03
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.85 min; [M+H]+=420.84.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1ccc(Br)cc1)OC
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a solution of 4-bromobenzenethiol (7.56 g; 40 mmol) in anhydrous acetone (50 mL) was added potassium carbonate (5.52 g, 40 mmol) and dropwise at room temperature 2-bromo-1,1-dimethoxy-ethane (4.7 mL, 40 mmol). After 24 h of stirring, the precipitate was filtered, the filtrate concentrated, the residue diluted with water and diethyl ether (150 mL), the organic layer washed successively with water (60 mL), NaOH 4N (30 mL) and water (60 mL), dried over Na2SO4 and concentrated to give 1-bromo4-(2,2-dimethoxy-ethylsulfanyl)-benzene (compound PRE12) (9.71 g; orange oil) (Yield=87%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[S:13][C:14]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[C:15]([C:17]([O:19]CC)=O)[N:16]=1.[CH3:30][NH2:31]>C1COCC1.O>[CH3:30][NH:31][C:17]([C:15]1[N:16]=[C:12]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[S:13][C:14]=1[NH:22][C:23]([C:25]1[CH:29]=[CH:28][S:27][CH:26]=1)=[O:24])=[O:19]
Reactant: CN
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccsc1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of ethyl 2-(naphthalen-2-ylamino)-5-(thiophene-3-carboxamido)thiazole-4-carboxylate (50 mg, 0.118 mmol) in THF (5 mL) was added 40% methylamine in water (0.5 mL) at rt, and the mixture was stirred overnight at rt. To complete the reaction, an additional 40% methylamine in water (0.5 mL) was added to the mixture, and stirring was continued at rt overnight. The solvent was removed, and the residue was triturated with water. The resulting solids were collected by filtration, and the solids were washed successively with water and EtOAc to give 28 mg (58% yield) of the titled compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]3[C:19](=[CH:20][C:6]=2[O:5]1)[CH:18]=[CH:17][CH:16]=[CH:15]3.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:22])[C:7]2[CH:13]=[C:14]3[C:19](=[CH:20][C:6]=2[O:5]1)[CH:18]=[CH:17][CH:16]=[CH:15]3
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2cc3ccccc3cc2C1=O
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2cc3ccccc3cc2C1=S

Procedure:
To a solution of 16.6 g (0.06 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepin-5(4H)-one in 150 ml of dry toluene was added a mixture of 8.6 g (0.045 mole) of phosphorus pentasulfide and 8.6 g of potassium sulfide which had been ground together. The reaction mixture was stirred and heated at reflux for 24 hr. The mixture was filtered hot and the filtrate concentrated under reduced pressure. Yellow solid, 6.5 g (35%) was obtained which was recrystallized from ethanol, m.p. 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17]O)=O)[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].C1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:45]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]2[S:45][CH2:17][C:16]([CH3:20])([CH3:19])[N:15]=2)[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2ccccc2Cl)n1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CSC(c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3ccccc3Cl)n2)=N1
Yield: 18.9 %

Procedure:
To a N2 purged 50 mL round bottom flask attached with condenser was added 1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-N-(1-hydroxy-2-methyl propan-2-yl)-1H-imidazole-4-carboxamide (361 mg, 646 μmol), anhydrous benzene (20 mL) and P2S5 (720 mg, 3.24 mmol). The reaction solution was stirred at reflux for 1.5 hr. The reaction solution was diluted with EtOAc (100 mL) and filtered through a Buchner funnel to remove excess P2S5. The filtrate was washed with aq. 0.1 N NaOH (60 mL) and H2O (100 mL). The partitioned organic phase was dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 12 g SiO2 column using a gradient of 100% hexane to 95% EtOAc to afford 68 mg (19% yield) of title compound. MS (ESI) 556.3, 558.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.10 (t, J=2.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79 (br s, 1H), 7.66-7.70 (m, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.43 (dd, J1 8.5=Hz, J2=2.0 Hz, 1H), 7.27-7.33 (m, 4H), 3.22 (s, 2H), 3.10 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([NH2:16])[N:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1>[NH2:16][C:4]1[N:3]=[C:2]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]=1
Reactant: CCCCCN
Reactant: Nc1ncc(CCc2ccccc2)c(Cl)n1
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)ncc1CCc1ccccc1
Reaction time: 8.5 h
Yield: 79.7 %

Procedure:
A mixture of 4-chloro-5-phenethylpyrimidine-2-ylamine (234 mg, 1 mmol), amylamine (0.58 ml) and dioxane (2 ml) was kept at 95-100° C. for 8.5 hours. The procedure according to pro-treatment of Example 27 was carried out to give the object compound (227 mg, 79.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Product: CC(C)S(=O)(=O)NCc1cncc(-c2cc3ccc(Cl)cc3n2C)c1

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and isopropylsulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.35 (d, J=6.8 Hz, 6H), 3.19-3.27 (m, 1H), 3.76 (s, 3H), 4.40 (s, 2H), 6.67 (d, J=0.6 Hz, 1H), 7.07 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.66 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 378.1036 [(M+H)+ Calcd for C18H21ClN3O2S: 378.1043].
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>CN(C)C=O.[Cl-].[Na+].O>[Br:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C2CC2)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
In a 250 ml round bottom flask was added (R)-N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (17, 3.2 g, 9.2 mmol) in N,N-dimethylformamide (31 ml). The mixture was cooled in ice bath, followed by addition of N-bromosuccinimide (1.477 g, 8.30 mmol) in portions. The mixture was stirred in ice bath for 30 min, at which point about ˜10% starting material remained. Another 0.1 equivalence (160 mg) of N-bromosuccinimide was added to the reaction mixture, which was stirred in an ice bath for another 30 min. Brine (200 ml) was added, followed by extraction with EtOAc (2×200 mL). Organic layers were combined. After drying and filtering, a suspension was obtained upon concentration. The solid was collected on a filtered, and then washed with 10 ml EtOAc. The resulting 2 g of filtrated solid was purified by silica gel column chromatography, eluting with 5-10% MeOH in EtOAc. Product-containing fractions were combined and concentrated to yield a solid which was washed twice with EtOAc (2×10 ml). The title compound (22, 0.62 g, 16%) was obtained as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 2 H) 1.05-1.13 (m, 2 H) 1.42 (s, 3 H) 3.42-3.54 (m, 3 H) 4.71 (t, J=5.81 Hz, 1 H) 4.99 (s, 1 H) 7.58 (d, J=8.59 Hz, 2 H) 7.62 (s, 1 H) 8.01 (d, J=8.59 Hz, 2 H) 8.48 (d, J=0.76 Hz, 2 H) 8.51 (d, J=0.76 Hz, 2 H) 10.63 (s, 1 H); ESI-MS: m/z 432 (M+H)+. Additional amounts of the title compound were obtained by combining filtrates and re-purifying them by silica gel column chromatography.
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:26]([C:23]4[N:22]=[CH:21][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:25][N:24]=4)=[O:27])[CH2:12]3)[C:6]=12
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: CC(C)c1cnc(C(=O)O)nc1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cnc(C(=O)N[C@H]2CCN(c3nccn4ccnc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a suspension of (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (84 mg, 0.3 mmol) and 5-isopropylpyrimidine-2-carboxylic acid (85 mg, 0.5 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (190 mg, 0.5 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 35 mg of the title compound (32% yield) as a white solid. MS: (ES) m/z found 352.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)CCC#Cc1ccc(Cl)cc1
Reactant: Nc1ncc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ncc(Cl)cc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 16.7 %

Procedure:
A mixture of 5-chloro-3-iodo-2-pyridinamine (Description 3, 2.31 g, 9.1 mmol), methyl 5-(4-chlorophenyl)-4-pentynoate (Description 2, 3.03 g, 13.6 mmol), triphenylphosphine (126 mg, 0.48 mmol), lithium chloride (385 mg, 9.1 mmol) and sodium carbonate (4.82, 45.5 mmol) in dimethylformamide (75 mL) was degassed with bubbling nitrogen, then palladium (II) acetate (102 mg, 0.45 mmol) was added and the mixture was stirred at 100° C. for 18 h. The mixture was cooled and further triphenylphosphine (126 mg, 0.48 mmol) and palladium (II) acetate (102 mg, 0.45 mmol) were added. The mixture was degassed with bubbling nitrogen and stirred at 100° C. for 6 h. The mixture was poured into saturated aqueous ammonium chloride and water and extracted with ethyl acetate. The combined organic fractions were washed with water and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10 increasing to 75:25), to give the title compound (530 mg, 17%). 1H NMR (360 MHz, CDCl3) δ 10.90 (1H, br s), 8.10 (1H, d, J 2.2 Hz), 7.92 (1H, d, J 2.2 Hz), 7.60-7.52 (4H, m), 3.64 (3H, s), 3.19 (2H, t, J 7.9 Hz), and 2.65 (2H, t, J 7.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[CH:6][N:5]2[C:27]=1[CH3:28].[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1>CC(C)=O>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:27]([CH3:28])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([NH:23][CH2:24][CH2:25][O:26][C:29](=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:22])[CH:8]=1)[CH3:20]
Reactant: O=C1CCC(=O)O1
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Solvent: CC(C)=O
Product: CCc1cccc(C)c1CNc1cc(C(=O)NCCOC(=O)CCC(=O)O)cn2c(C)c(C)nc12
Yield: 227.9 %

Procedure:
2,3 dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-hydroxyethyl-imidazo[1,2-a]pyridine-6-carboxamide (250 mg, 0.263 mmol) and succinic anhydride (100 mg, 1.00 mmol) were added to 7 ml of acetone. The mixture was refluxed for 48 h. The presiptated product was filtered off and washed with acetone and ether to give 288 mg (91%) of the title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Br:35])=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (230) (7.9 g, 14.64 mmol) in tetrahydrofuran (200 mL) was added an aqueous solution (100 mL) of LiOH.H2O (6.15 g, 146.44 mmol). The resulting mixture was refluxed for 16 h. After completion of the reaction the organic solvent was removed on a rotary evaporator and water (30 mL) was added. The aqueous solution was acidified (pH 5) with concentrated HCl at 0° C. to give a white solid which was filtered off. The solid residue was triturated in diethyl ether and filtered. After drying, 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (231) was obtained (6.3 g, 89%) as a white solid.