Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[S:24])[NH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([F:41])=[C:37]([CH:40]=1)[C:38]#[N:39]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([S:24][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:41])=[C:37]([CH:40]=3)[C:38]#[N:39])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c[nH]c(=S)n1-c1ccc(F)cc1
Reactant: N#Cc1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(F)c(C#N)c2)n1-c1ccc(F)cc1
Yield: 86 %

Procedure:
To a pre-stirred mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (1.50 g, 3.93 mmol) and K2CO3 (0.82 g, 5.90 mmol) in acetone (60 mL) was added 5-(bromomethyl)-2-fluorobenzonitrile (1.09 g, 5.11 mmol), and the reaction mixture was heated at reflux 2 h. After cooling, the reaction mixture was filtered through Celite™ and concentrated. Purification by flash chromatography (Hex/EtOAc, 2:1) afforded the title product (1.74 g, 3.38 mmol, 86%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 1.53 (s, 6H) 4.21 (s, 2H), 6.36 (m, 2H), 6.84 (m, 3H), 6.96 (s, 1H), 7.11 (t, 1H), 7.18 (s, 1H), 7.26 (d, 1H), 7.52 (m, 2H); MS (EI) m/z 514 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.C(O)(=O)C.[CH2:32]1[C:35]2([CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:34][O:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[CH2:32]1[C:35]2([CH2:40][CH2:39][CH2:38][N:37]([CH2:8][C:7]3[C:2]([Cl:1])=[C:3]([NH:12][C:13]4[N:18]=[C:17]([NH:19][CH:20]5[CH2:21][CH2:22]5)[C:16]5=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]5[N:14]=4)[CH:4]=[C:5]([C:10]#[N:11])[CH:6]=3)[CH2:36]2)[CH2:34][O:33]1
Reactant: C1CNCC2(C1)COC2
Reactant: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(CN2CCCC3(COC3)C2)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 400) (20 mg, 0.053 mmol), acetic acid (9.07 tli, 0.158 mmol) and 2-oxa-6-azaspiro[3.5]nonane (16.79 mg, 0.132 mmol) in THF (0.5 ml) was stirred at room temperature to for 5 min. to achieve solution. DCE (0.5 mL) was added and after 25 min, sodium triacetoxyborohydride (33.6 mg, 0.158 mmol) was added. LCMS analysis found the desired mass of the product. The mixture was stirred overnight. The reaction mixture was then quenched with saturated aqueous NaHCO3 and stirred for 10 minutes. It was dried with a stream of nitrogen and then dissolved in DMF (1.5 mL) and purified by reverse-phase preparative LCMS.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:20])[CH:8]=2)[CH2:5][C@H:4]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:3]1.Cl.CN(C)CCCN=C=NCC.[CH:38](O)=[O:39]>O1CCCC1.O.C(Cl)Cl>[CH:38]([N:16]1[CH2:17][CH2:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:20])([F:19])[CH2:14][CH2:15]1)=[O:39]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3(F)CCNCC3)c(F)c2)C(=O)O1
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(F)CCN(C=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (S)-3-N-[[2-oxo-3-[4-(4-fluoro-4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 74, Step 5, 205 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg) and formic acid (28 μL) in dry tetrahydrofuran (11.6 mL) is diluted with water to solubilize all reactants and stirred at ambient temperature for 6 hrs. The reaction is then diluted with methylene chloride (30 mL), washed with water (20 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 40 g), eluting with a gradient of methanol/methylene chloride (3/97-5/95). Those fractions with an Rf=0.40 by TLC (methanol/chloroform, 10/90) are pooled and concentrated and the residue is recrystallized from chloroform/diethyl ether to give the title compound, mp 180-181° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[CH:61]=[CH:60][N:59]=[C:58]([NH2:62])[N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:58]1[N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[CH:61]=[CH:60][N:59]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(Nc2ccnc(N)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4ccnc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N4-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])N=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C2CC2)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[C:14]([CH3:15])=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: ClCc1nnnn1C1CC1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC5(COC5)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as white solid. MS (m/e): 397.3 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].C(OC(=O)C)(=O)C.[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[N+:26]([C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][C:13]=1[C:14]=23)([O-:28])=[O:27]
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc([N+](=O)[O-])c3c2C1(CCCCBr)CCC3
Temperature: 15 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A 100 mg (0.32 mmol) portion of 2a-(4-bromobutyl)-2a,3,4,5-Tetrahydrobenz [cd] indole-2 (1H) -one was dissolved in 2 ml of acetic acid, and the resulting solution was cooled to 15° C. Thereto was added acetic acid solution (1 ml) containing 46 al (0.48 mmol) of acetic anhydride and 19 μl (0.48 mmol) of nitric acid, and the mixture was stirred overnight at 15° C. The reaction solution was extracted with chloroform and washed with water and sodium bicarbonate aqueous solution in that order. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (20 cc; elution with ethyl acetate-hexane=1:2) to obtain 83 mg of the title compound (73% in yield). 1H-NMR (CDCl3): δ 1.25 (1 H, m), 1.46 (2 H, m), 1.73-2.02 (5 H, m), 2.18 (2 H, m), 3.24 (2 H, m), 3.33 (2 H, t), 6.89 (1 H, d), 8.15 (1 H, d), 9.07 (1 H, s). EI m/z 352, 354 (1:1) (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][C:27](F)=[CH:28][CH:29]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][C:27]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[CH:28][CH:29]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3cc(-c4ccc(F)nc4)ccn23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(-c3ccn4c(-c5ccc(CNC(=O)OC(C)(C)C)cc5)cnc4c3)cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Dissolve {4-[7-(6-fluoro-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-carbamic acid tert-butyl ester (0.500 g, 1.19 mmol, 1.0 eq.) and N-methyl piperazine (0.53 mL, 4.78 mmol, 4.0 eq.) in DMSO (20 mL). Add K2CO3 (0.330 g, 2.0 eq.). Stir the reaction mixture at 80° C. overnight. Pour the mixture into 20 mL of ice. Filter the solid, and purify by silica gel chromatography with a 0-5% MeOH/DCM gradient to give the title compound 0.408 g (0.82 mmol, 70%) as a slightly yellow solid. Use the solid directly in the reaction B below: MS(ES), m/z 499 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1.O>[C:1]1([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]([C:26]([OH:28])=[O:27])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: c1ccc(N2c3ccccc3Cc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2N(c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
A solution of N-phenylacridan (14.15 g, 55 mmol) in 200 mL of dry THF under inert atmosphere was cooled to −78° C. and 33.0 mL of 2.5 M n-butyllithium in hexanes (82.5 mmol) was added dropwise over 20 minutes. The solution was stirred at −78° C. for 30 minutes and then warmed to room temperature over 35 minutes. The reaction mixture was again cooled to −78° C. and 350 g of crushed dry ice was added causing a precipitate to form. The reaction was allowed to slowly warm to room temperature causing the reaction to become homogeneous. Stirring under argon was continued at room temperature. The resultant precipitate was collected by suction filtration. The solid was dissolved in 100 mL of water, which was acidified to pH 3 with 2N HCl and extracted with 4×200 mL of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to dryness to afford 8.72 g of crude product. The reaction mixture filtrate was also concentrated to dryness to afford a solid that was taken up in 300 mL of water. The aqueous solution was acidified, extracted with 3×200 mL of methylene chloride and the combined organics were dried over sodium sulfate and concentrated to afford a second crop of 3.44 g of N-phenylacridan-9-carboxylic acid (73.4%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Yield: 82.2 %

Procedure:
A suspension of 2-butyl-4-chloro-1H-imidazole-5-methanol (22.0 g) in dichloromethane:1,4-dioxan (2:1) (690 ml) was treated with manganese dioxide (63.15 g) and the reaction mixture heated at reflux under nitrogen for 3.5 h. The reaction mixture was cooled, filtered and the filtrate evaporated to leave an off-white solid. The residue was triturated with petroleum ether, filtered and dried to give the title compound as a white solid (17.9 g) m.p. 98°-99° C.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([O-:29])=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1.[Na+].O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:29])=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: O=Cc1cccnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A suspension of 2-chloronicotinaldehyde (228 mg, 1.62 mmol) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (500 mg, 1.62 mmol) in DMSO (2.5 mL) was heated for 12 hours at 80° C. The reaction was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 35-60% ethyl acetate/isohexane, to give the title compound as solid (349 mg). 1H NMR (400 MHz, d6-DMSO): δ 11.00 (1H, s), 8.84-8.82 (2H, m), 8.40-8.34 (3H, m), 8.25 (1H, d, J=8.7 Hz), 8.06-8.02 (2H, m), 7.94-7.84 (3H, m), 7.38 (2H, t, J=8.8 Hz).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccc(Cl)nc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(Cl)nc3)cc2)c1

Procedure:
3-[4-(6-Chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-chloropyridine-5-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=340.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.CO.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]Cl>[OH-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH2:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)([CH2:17][C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=C1C(Cc2ccncc2)c2cccnc2N1c1ccc(Cl)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1N(c2ccc(Cl)cc2)c2ncccc2C1(Cc1ccncc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1,3-dihydro-1-(4-chlorophenyl)-3-(4-pyridinylmethyl)-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g, 8.93 mmol) in 20 ml 1N NaOH was treated with enough MeOH to effect solution. The solution was treated dropwise with a solution of 2-picolylchloride hydrochloride (1.6 g, 9.82 mmol) in 10 ml water over 10 min. The mixture was stirred at room temperature for 16 h, and the resulting solid was colledted by filtration, washed with water, and dried. The solid was recrystallized from CHCl3 --C6H12 to give the desired product in 79% (3.0 g) yield : m.p. 193°-195° ; 1H NMR (300 MHz, CDCl3TMS) δ [3.34 (d, J=12, 1H), 3.56 (d, J=12, 1H) CH2 -(2-Pyr)], [3.48 (d, J=14, 1H), 3.78 (d, J=14, 1H) CH 2 -(4-Pyr)], [6.95 (m, 1H), 8.0 (m, 1H), 8.27 (d, J=7, 1H) Pyr], [7.0 (m, 6H), 7.5 (m, 2H) 2-Pyr & 4-Cl-Phe]), [7.42 (d, J=7, 2H), 8.32 (d, J=7, 2H) 4-Pyr]; IR (Nujol) 1732 (C=O) cm-1 ; MS (NH3 -CI) m/e 427(M+1)/100; Analysis calc'd for C25H19N4OCl H2O: C, 67.49; H, 4.76; N, 12.59; found: C, 67.38; H, 5.01; N, 12.34.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:2]3[C:7]4=[CH:8][N:9]([C:11]5[C:12]([C:13]#[N:14])=[CH:15][CH:16]=[CH:17][C:18]=5[Cl:19])[N:10]=[C:6]4[C:5]([F:20])=[CH:4][N:3]=3)=[CH:36][CH:37]=2)[CH2:31]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N)nc2)C1
Reactant: N#Cc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(F)c4nn(-c5c(Cl)cccc5C#N)cc34)nc2)C1
Temperature: 80 °C
Yield: 64.1 %

Procedure:
A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile (106 mg, 0.3 mmol), 3-(6-aminopyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (57 mg, 0.35 mmol), Pd2(dba)3 (7 mg, 0.0075 mmol), Xantphos (17 mg, 0.03 mmol) and cesium carbonate (196 mg, 0.6 mmol) in dioxane (3.0 mL) was degassed and purged with nitrogen. The reaction mixture was heated at 80° C. overnight. After cooling to room temperature, the resultant mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50-60% ethyl acetate in cyclohexane) to afford the title compound as a brown solid (100 mg, 64% yield). LCMS (Method C): RT=2.54 min, m/z: 520 [M+H+].
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([NH:32][C@H:33]([C:39]([NH:41][C@H:42]([C:60]([NH:62][C@H:63]([C:66]([NH:68][C@H:69]([C:72]([OH:74])=[O:73])[CH2:70][OH:71])=[O:67])[CH2:64][OH:65])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([NH:32][C@H:33]([C:39]([NH:41][C@H:42]([C:60]([NH:62][C@H:63]([C:66]([NH:68][C@H:69]([C:72]([OH:74])=[O:73])[CH2:70][OH:71])=[O:67])[CH2:64][OH:65])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1

Procedure:
600 Milligrams of Z-Leu-Gly-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH was dissolved in 50 ml of methanol and 10 ml of 10%-acetic acid, then the mixture was subjected to catalytic reduction in the presence of 500 mg of palladium at a room temperature under an atmospheric pressure to obtain H-Leu-Gly-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[N:13][NH:14][CH:15]=2)=[N:9][CH:10]=1)[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH2:17]([O:16][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[N:14][N:13]([CH3:19])[N:12]=2)=[N:9][CH:10]=1)[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CCOC(OCC)c1ccc(-c2c[nH]nn2)nc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(OCC)c1ccc(-c2cnn(C)n2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
In acetonitrile (25 mL) was dissolved 5-(diethoxymethyl)-2-(1H-1,2,3-triazol-4-yl) pyridine (1.34 g, 5.40 mmol) obtained in Step 4. To the solution were added potassium carbonate (2.24 g, 5.40 mmol) and iodomethane (0.405 mL, 6.48 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 5-(diethoxymethyl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (698 mg, 49% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]2[C:10](C#N)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH2:19]>Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:1]([O:2][CH2:3][CH3:4])=[O:19])=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C=Cc2ccccc2C#N)cc1
Reactant: O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C=Cc2ccc(OC)cc2)cc1
Reaction time: 6 h

Procedure:
4'-Methoxystilbenenitrile, 72.5 g. [Neher et al., Helv. Chim. Acta 29, 449-67 (1946)] in 1 liter of 5N hydrogen chloride in ethanol was heated under reflux for eight hours. An additional 100 ml. of 10N hydrogen chloride in ethanol was added and refluxing continued for about sixteen hours. An additional 100 ml. of 10N hydrogen chloride in ethanol was then added and refluxing continued for six hours. The reaction mixture was diluted with 2 liters of water, and the solid product which separated was collected by filtration and air-dried. The product was dissolved in methylene dichloride, dried over anhydrous magnesium sulfate and the solvent removed to give 73 g. of ethyl 4-(4-methoxystyryl)benzoate, m.p. 191°-192° C. when recrystallized from ethanol.