Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([OH:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([O:21][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 19 h

Procedure:
1-(2-Chloro-ethoxy)-2-nitro-benzene (10 g) and 5-fluoro-2-nitro-phenol (7.86 g) were dissolved in 50 ml DMF and was stirred for 19 h at 90-110° C. after careful addition of 13.82 g potassium carbonate. The reaction mixture was poured in a mixture of crushed ice and water (500 ml) which was vigorously stirred. The residue was filtered off, washed several times with water and dried. The crude product was suspended in methanol and the pale yellow residue was again filtered off, washed with methanol and dried. Yield: 9.5 g.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][N:25]=1)[N:22]=[CH:21][C:20]([C:26]#[N:27])=[C:19]2[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1.C(Cl)(=O)C#CC>O1CCCC1.N1C=CC=CC=1>[Br:35][C:31]1[CH:30]=[C:29]([NH:28][C:19]2[C:18]3[C:23](=[CH:24][N:25]=[C:16]([NH:15][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:17]=3)[N:22]=[CH:21][C:20]=2[C:26]#[N:27])[CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1cnc2cnc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC#CC(=O)O
Agent: CC#CC(=O)Cl
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Reaction time: 72 h
Yield: 8.4 %

Procedure:
To 100 mg of butynoic acid in 5 mL of anhydrous tetrahydrofuran under an inert atmosphere at 0° C. was added 0.23 mL on N-methyl morpholine and 0.15 mL of isobutyl chloroformate. This solution was then added to 150 mg of 6-amino-4-(3-bromo-phenylamino)-[1,7]naphthyridine-3-carbonitrile in 3 mL of pyridine at 0° C. After standing at 0° C. for three days, a second portion of butynoyl chloride was added. After an additional 8 hours the reaction was stripped of solvents on a rotary evaporator and the crude product was purified by flash chromatograph using a gradient of 0-20% methanol/chloroform to give 15 mg of but-2-ynoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1,7]naphthyridin-6-yl]-amide: melting point 255° C. (decomposed); mass spectrum (m/e): M+H 406.1, 408.2.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2.[CH:30]([B-](F)(F)F)=[CH2:31].[K+].C(N(CC)CC)C>C(O)C.OS([O-])(=O)=O.[K+]>[CH:30]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2)=[CH2:31]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Br)c3C2)CN1C(=O)OC(C)(C)C
Reactant: C=C[B-](F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Temperature: 25 °C

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (10.0 g, 21.3 mmol) in ethanol (200 mL) was added potassium vinyltrifluoroborate (4.28 g, 32 mmol) and triethylamine (4.5 mL, 32 mmol) followed by dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloromethane adduct (175 mg, 0.21 mmol). The reaction mixture was heated to reflux for 6 h, cooled to room temperature, diluted with 10% aqueous KHSO4 and the ethanol removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc and the organic phase washed with brine, dried over Na2SO4, solvent evaporated and crude product purified by chromatography on silica eluting with 40-60% EtOAc/hexane to give, after evaporation, the title compound (8.18 g). LRMS (ESI) m/z 417.2 [(M+H)+; calcd for C22H29N2O6: 417.2].
Reaction SMILES: [SH:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.O.O(C(C)(C)C)[Na].[Br:35][C:36]1[C:44](I)=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1>[Cu]I.CN(C=O)C>[Br:35][C:36]1[C:44]([S:1][C:2]2[NH:10][C:9]3[C:4](=[N:5][CH:6]=[N:7][C:8]=3[NH2:11])[N:3]=2)=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1
Reactant: Nc1ncnc2nc(S)[nH]c12
Reactant: Brc1cc2c(cc1I)OCO2
Agent: [Cu]I
Agent: CC(C)(C)O[Na]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2nc(Sc3cc4c(cc3Br)OCO4)[nH]c12
Temperature: 110 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
8-Mercaptoadenine (602 mg, 3.6 mmol), neocuproine hydrate (81 mg, 0.36 mmol), CuI (69 mg, 0.36 mmol), NaO-t-Bu (692 mg, 7.2 mmol), 5-bromo-6-iodo˜benzo[1,3]dioxole (3.53 g, 10.8 mmol) and anhydrous DMF (24 mL) were charged in a nitrogen box. The vessel was sealed with Teflon tape, placed in an oil bath (110° C.) and magnetically stirred for 24 h. The solvent was removed under high vacuum and the crude purified by column chromatography on silica gel (EtOAc:CH2C12:MeOH at 2:2:1) to provide the product (1.29 g, 97%). 1H NMR (400 MHz, acetone-d6) 8.07 (s, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 7.08 (bs, 2H), 6.13 (s, 2H); MS m/z 366.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[CH3:10].C([Mg]Cl)(C)C.[C:16](=[O:18])=[O:17]>O1CCCC1>[F:9][C:4]1[C:3]([CH3:10])=[C:2]([CH:7]=[CH:6][C:5]=1[F:8])[C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: Cc1c(Br)ccc(F)c1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid was synthesised as reported in US 2005/0054733A1 and described below 1-bromo-3,4-difluoro-2-methylbenzene (I67) (8.07 g, 39.0 mmol) was cooled to 0° C. in tetrahydrofuran (THF) (40 mL). Isopropylmagnesium chloride (29.2 mL, 58.5 mmol) was added dropwise and the solution stirred at room temperature overnight. The solution was cooled to 0° C. and gassed slowly with Carbon dioxide (excess) for 1 hour. The cooling was removed and gassing continues for 4 hours before allowing the solution to stand at room temperature overnight. Water (10 ml) was added and the solvents removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and 2N Hydrochloric acid (25 mL). The aqueous phase was extracted with ethyl acetate (5×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to a crude solid that was recrystalised from cyclohexane to afford product in 4.68 g.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:22][OH:23])=[N:7]2.[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:13]([O:15][CH3:24])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:22][OH:23])=[N:7]2
Reactant: Cc1cc2nc(CO)ccc2c(Br)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of (S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (3.6 g, 9.4 mmol) in anhydrous dichloromethane and methanol (1:1, 20 mL) was added (trimethylsilyl)diazomethane (2 M in hexanes, 5.17 mL, 10.34 mmol) and the reaction was stirred at room temperature for three hours. An additional 2 mL of (trimethylsilyl)diazomethane was added and stirred for 2 hours, followed by an additional 1 mL of (trimethylsilyl)diazomethane for 1 hour, then 1 mL of (trimethylsilyl)diazomethane added and let go overnight. An additional 3.5 mL of (trimethylsilyl)diazomethane were added and stirred for 1 hour. The reaction was quenched with 30 mL of acetic acid and then stirred 15 minutes. The reaction was concentrated under reduced pressure and then absorbed onto silica. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow foam (2.37 g). LCMS-ESI+ (m/z): [M+H]+ calcd C18H23BrNO4: 396.07. found: 396.71.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:20][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)Cc1cc(CCC(C)=O)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In 50 ml of acetone was dissolved 2.17 grams of 4-(7-hydroxy-2-fluorenyl)-butan-2-one, then 1.43 grams of potassium carbonate (anhydrous) was added, and heated to reflux for 2 hours after addition of an excess of methyl iodide. The mixture was stirred at room temperature for overnight and acetone was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with magnesium sulfate, and ethyl acetate was removed therefrom by evaporation in vacuo. The residue was subjected to a silica gel column chromatography, eluted with a 4:1 mixture of n-hexane and ethyl acetate, and the resulting crystals were recrystallized from methanol to give 1.15 grams of 4-(7-methoxy-2-flourenyl)-butan-2-one, white crystals, m.p. 100°-101° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][OH:17].[H-].[Na+].[CH3:20]I>C1COCC1.CCOCC>[Br:1][C:2]1[C:3]([CH2:16][O:17][CH3:20])=[CH:4][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1cc(CO)c(Br)c(OCOC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1cc(COC)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of (2-bromo-3,5-bis-methoxymethoxy-phenyl)-methanol (7.68 g, 24.94 mmol) in THF (50 mL) was added NaH at 0° C. The mixture was stirred at room temperature for 20 minutes then MeI (7.84 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with ether (50 mL), filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-bromo-1,5-bis-methoxymethoxy-3-methoxymethyl-benzene (5.66 g, 70%). 1H NMR (400 MHz, CDCl3δ 6.90 (s, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 5.25 (s, 2H), 5.20 (s, 2H), 4.50 (s, 23.77 (s, 3H), 3.40 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23]([C:41]3[CH:40]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:43][CH:42]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Yield: 71.8 %

Procedure:
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (350 mg, 0.75 mmol), potassium carbonate (311 mg, 2.25 mmol), 4-triflouromethoxylphenyl boronic acid (311 mg, 1.5 mmol) and tetrakis-(triphenylphosphine)palladium (87 mg, 0.075 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[3-Methyl-1-(4′-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzoylamino}-propionic acid methyl ester (294 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(N)cc1Cl
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cc1Cl
Yield: 32.8 %

Procedure:
The 2-chloro-4-aminobenzonitrile (57 g, 0.37 m) was added to a cold stirred solution of concentrated sulfuric acid (115 g) in water (1,000 ml). Then a cold solution of sodium nitrite (26.5 g, 0.38 m) in water (250 ml) was added to the suspension solution at a temperature between 0° and 6° C. Upon addition of the sodium nitrite, stirring continued for approximately three hours at which time urea (3 g) was added to the reaction mixture. The reaction mixture reacted at a temperature between 69° and 76° C. for approximately three hours. The reaction product was filtered and crystallized from water to yield the fifth step product 2-chloro-4-hydroxybenzonitrile (18.8 g, 33%, mp 157°-158° C.).
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:29])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:21]=2)=[CH:13][CH:12]=1>>[CH3:29][C:19]1[O:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[CH:12][CH:13]=2)=[N:21][C:20]=1[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1cncnc1
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 5-Pyrimidine boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 335.2 (M+1)
Reaction SMILES: B([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])(O)O.[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.[Cl-].[Na+].O>[Cl:18][C:19]1[N:20]=[C:21]([C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:22]=[N:23][CH:24]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Cl)n2)c1
Temperature: 25 °C

Procedure:
To a stirred mixture of the title compound from Example 1 (3.9 g, 0.017 mol), 2,6-dichloropyrazine (10.0 g, 0.067 mol) and tetrakis(triphenylphospine)-palladium(0) (0.05 g) in glyme (ethylene glycol dimethyl ether, 150 mL) was added aqueous 1M sodium carbonate (67 mL), 0.067 mol). The mixture was heated to reflux and for 8 h. After cooling to room temperature, the mixture was poured into brine (300 mL). The layers were separated and the aqueous phase extracted with three 150 mL-portions of ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate/hexane to furnish 4.0 g (78% of theory) of the title compound as a white solid melting at 80°-83° C. 1H NMR (300 MHz, CDCl3) δ 10.75 (br s, 1H), 8.91 (s, 1H), 8.51-8.56 (m, 1H), 8.39-8.41 (m,1H), 7.46 (s, 1H), 7.29-7.33 (m, 1H), 2.40 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[C:24]2[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.CCN(CC)CC>CCCCO>[CH3:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[C:24]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=1)[CH3:3])=[CH:13]2
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cc(C#N)c34)n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (208 mg, 0.75 mol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (compound 5505) (160 mg, 0.90 mmol) and Et3N (228 mg, 2.25 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture stirred at 150° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 50% Hex/EA) to afford the desired product, (S)-4-(1-(8-methyl-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5506, compound 264 in Table 4) (90 mg, 28% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][C@@H:22]3[CH2:26][O:25]C(C)(C)[O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][C@@H:22]([OH:23])[CH2:26][OH:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC[C@@H](CN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)O1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C[C@@H](O)CO)CC1
Reaction time: 10 h
Yield: 89.5 %

Procedure:
A solution of 4.16 g (9.72 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-[1,4]diazepan-5-one in 35 ml of methanol and 3.8 ml of water was treated with 1.95 g of Dowex 50WX8 (activated with aqueous 25% HCl and washed neutral wit water). The reaction was stirred for 10 h at reflux temperature, cooled, evaporated, dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 3.37 g (89%) of the title compound as light yellow foam. MS: 387.1 (MH+, Cl).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1>N1C=CC=CC=1>[C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:9][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Ethyl chloroformate (30 g, 0.276 mol) was added at 0° C. to 4-amino-1-phenylmethylpiperidine (50 g, 0.262 mol) in pyridine (600 mL). After the addition, the mixture was kept at room temperature overnight, and the pyridine was then evaporated. The residue was extracted with methylene chloride; and the resulting solution washed with water, dried over sodium sulfate, and the methylene chloride evaporated to dryness. The residue was dissolved in diisopropyl ether. A white product precipitated, which was isolated by filtration to yield 42.71 g (62%) of ethyl (1-phenylmethyl-4-piperidyl)-carbamate, m.p. 100° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH:23]=[CH2:24]>>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:24][CH:23]=[CH2:22])[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Product: C=CCC1C(=O)N(Cc2ccccc2)c2ccccc2N=C1C
Yield: 85 %

Procedure:
Using 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one and 3-bromopropene, the titled compound was synthesized in substantially the same manner as in Working Example 21 as an oily product in a yield of 85%.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[CH:21]1([CH2:24][C:25]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)([NH2:27])[CH3:26])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C:25]([NH:27][C:11]([C:8]2[CH:7]=[C:6]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:10][N:9]=2)=[O:13])([CH3:26])[C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH2:23][CH2:22]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CCC1)C(F)(F)F
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclobutyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 110e) and 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (Example 66d) as starting materials and isolated (85 mg, 68%) as colorless oil; MS (ESI, m/z): 453.6 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:21]1([NH2:28])[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[C:21]1([NH:28][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])[CH:26]=[CH:25][C:24]([NH:27][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])=[CH:23][CH:22]=1
Reactant: Nc1ccc(N)cc1
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Product: N#Cc1ccc(-c2nc3cc(C(=O)Nc4ccc(NC(=O)c5ccc6[nH]c(-c7ccc(C#N)cc7)nc6c5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 281 was prepared according to the procedure similar to that described in Scheme V from 2-(4-cyanophenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C36H22N8O2: 599.19; found: 598.97.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.C1CCN2C(=NCCC2)CC1>C1COCC1>[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccccc1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Ic1ccccc1Cn1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.4 %

Procedure:
To a stirring solution of 1,2,4-triazole (1.02 g, 14.8 mmol) and 2-iodobenzyl bromide (6.05 g, 20.3 mmol) in THF (10 mL) was added a solution of DBU (2.65 g, 17.4 mmol) in THF (2 mL) dropwise over a 1 hour period. The mixture was stirred at ambient temperature for 12 hours after which it was filtered. The filtrate was concentrated in vacuo and the resultant residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 50-60% ethyl acetate/isohexane to give the title compound as a white solid (1.45 g). 1H NMR (360 MHz, CDCl3): δ 8.15 (1H, s), 8.00 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.36 (1H, t, J=7.6 Hz), 7.13 (1H, d, J=7.7 Hz), 7.08-7.04 (1H, m), 5.43 (2H, s).