Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.CO[CH:17]([O:20][CH3:21])[O:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:6]1[CH:9]=[C:2]([F:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(F)cc1C(OC)OC

Procedure:
A mixture of 0.210 g (1.06 mmole) of 5-fluoro-2-methoxy-4-nitro-benzaldehyde (IV.46c), 1 mL of trimethylorthoformate, 0.025 g of p-toluenesulfonic acid monohydrate and 5 mL of methanol was heated at reflux for one hour. The mixture was cooled, neutralized by addition of saturated sodium bicarbonate solution and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.243 g of 1-dimethoxymethyl-5-fluoro-2-methoxy-4-nitro-benzene (IV.46d) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:1][C:2]1[N:3]=[CH:4][C:5](/[CH:43]=[CH:42]/[C:41]([O:45][CH2:46][CH3:47])=[O:44])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(I)cnc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(Br)c(C)c1
Temperature: 90 °C

Procedure:
To a solution of 2-bromo-5-iodo-3-methylpyridine (1.5 g) in DMF (15 mL) was added palladium(II) acetate (56.5 mg) and tri-o-tolylphosphine (230 mg) and diisopropylethylamine (3.5 mL), and ethyl acrylate (1.09 mL). The mixture was heated at 90° C. for 1 hour. Resulting mixture was poured into water and extracted with AcOEt. The organic layer was washed with water and brine, and dried over Na2SO4, and the solvent was removed in vacuo. Residual brown oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:4-1:2) to give ethyl (2E)-3-(6-bromo-5-methyl-3-pyridyl)acrylate (1.00 g) as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([SH:10])=[N:9][C:5]=2[CH:4]=1.Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([S:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([S:23][CH2:24][CH2:25][C:26]4[S:30][CH:29]=[N:28][C:27]=4[CH3:31])[CH:19]=[CH:18][N:17]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: Cc1ncsc1CCSc1ccnc(CCl)c1C
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(SCc3nccc(SCCc4scnc4C)c3C)nc2c1

Procedure:
Following the procedure described in Example 1, the reaction of 5-methoxy-2-mercapto-1H-benzimidazole with 2-chloromethyl-3-methyl-4-[2-(4-methyl-5-thiazolyl)ethylthio]pyridine hydrochloride and aqueous sodium hydroxide solution gives the title compound as a yellow oil, from which a hydrochloride salt of the title compound is obtained as a colorless powder of m.p. 165° C (decomp.) by following the procedure described in Example 4.
Reaction SMILES: C[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:18]([Li])CCC.C([Li])(C)(C)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCCCCC.O>[C:28]1([N:34]([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:35](=[O:36])[CH3:18])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [Li]CCCC
Reactant: O=C=Nc1ccccc1
Reactant: Cc1[nH]c2ccccc2c1Sc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(=O)N(c1ccccc1)c1[nH]c2ccccc2c1Sc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2-Methyl-3-phenylthioindole (0.50 g, 2.1 mmol) (prepared according to the procedure described by Atkinson, J. G., et al., Synthesis, p. 480-481 (1988), was dissolved in dry tetrahydrofuran and cooled under nitrogen to -78° C. A solution of n-butyllithium in hexane (0.83 mL, 2.5M) was added via syringe. Carbon dioxide was bubbled into the reaction mixture over a period of several minutes; unreacted carbon dioxide was removed by freezing the reaction at liquid nitrogen temperature under high vacuum and warming to -78° C. A solution of t-butyllithium in hexane was added (1.35 mL, 1.7M) and the reaction stirred for 20 min. Phenylisocyanate (0.23 mL, 2.1 mmol) in tetrahydrofuran (1.5 mL) was added and the reaction stirred at 20° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over magnesium sulfate. Filtration and evaporation of solvent left an amber oil. The crude products were chromatographed on silica gel eluting successively with 15%, 20%, and 40% ether in hexane. 2-(N-Phenylacetamido)-3-phenylthioindole was isolated as a solid, mp 66°-68° C. Anal. Calc. for C22H18N2OS: C, 72.98; H, 5.01; N, 7.73. Found: C, 72.99; H, 4.87; N, 7.52 . Later fractions contained 2-(N-phenylacetamido)-1-(phenylcarbamoyl)-3-phenylthioindole, mp 123°-125° C. Anal. Calc. for C29H23N3O2S: C, 70.28, H, 4.67, N, 8.47. Found: C, 70.37, H, 4.61; N, 8.34.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:14]=[C:15]([C:19](=O)[CH2:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][C:21](=[O:22])[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(Br)c1
Solvent: CC(=O)O
Product: O=C1CC(c2cccc(Br)c2)=Nc2ccc([N+](=O)[O-])cc2N1
Temperature: 110 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
To a stirred solution of 4-nitrobenzene-1,2-diamine 2 (1.0 g, 6.53 mmol) in acetic acid (20 mL) was added ethyl 3-(3-bromophenyl)-3-oxopropanoate 1 (1.75 g, 6.53 mmol) at RT under inert atmosphere. The resulting reaction mixture was heated to 110° C. and stirred for 12 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude was purified by silica gel column chromatography (eluent: 25% EtOAc/Hexane) to afford compound 3 (0.91 g, 39.5%) as yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 10.91 (bs, 1H), 8.25 (s, 1H), 8.09-8.01 (m, 3H), 7.82 (d, J=6.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57-7.48 (m, 1H), 3.67 (s, 2H). MS (ESI): 361 [M+1]+
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Si:12]([O:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1.O.Cl[Pd]Cl>[Si:12]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:3]2[CH:2]=[C:11]3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8][CH:9]=[CH:10]3)[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(B(O)O)c1
Reactant: Ic1cccc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccccc3c2)c1
Reaction time: 24 h
Yield: 137.5 %

Procedure:
12 ml of THF/H2O was added to 0.6199 g (2.44 mmol) of iodonaphthalene, and 0.122 g (5 mol %) of PdCl2 (dppf) was added in a darkroom. 1 g (2.44 mmol) of 3,5-bis-tert-butyldimethylsilyloxymethyl Phenylboronic acid dissolved in 12 ml of THF/H2O was added, 3.66 ml (3 eq) of 2N NaOH aq was injected, the reaction was initiated in a 65° C. oil bath with light shielding, and the mixture was agitated for 24 hours. Completion of the reaction could not be confirmed because the raw material iodonaphthalene overlaps the target product in TLC (Hex only). Fluorescence was confirmed with the naked eye. This was extracted with EtOAc, and the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure to obtain 1.6530 g of a mixture of the target product and iodonaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]2[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=2)[C:52]([OH:54])=[O:53])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]3[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=3)[C:52]([OH:54])=[O:53])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(Cc2cccc(C(=O)O)c2)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)O)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 760 mg, 2.30 mmol) was dissolved in methylene chloride (10 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.15 mL, 2.30 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (0.536 mL, 4.6 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid (500 mg, 2.30 mmol) was added as a pre-dissolved reaction in methylene chloride (10 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Recrystallization from 17% ethyl acetate/methylene chloride afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (684 mg, 56%) as a white powder: ESI-LRMS m/e calcd for C26H28ClN3O5S [M+] 529.14, found 530.26 [M+H+].
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.[I-].[Na+].[Na].[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1>CC#N.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: c1nc[nH]n1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCn4cncn4)cc3n2C2CCC2)cc1)C1CC1
Yield: 14.5 %

Procedure:
To a solution of {4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH3CN (10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC to give {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.C(OCC)(=O)C>ClC1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]2=3)=[O:3])[CH2:23][CH2:22]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CN1CCC(O)CC1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCC(OC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
A quantity of 4.1 gm (0.015 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was refluxed with 3.45 gm (0.03 mol) of 1-methyl-4-piperidinol in 50 ml of chlorobenzene for two hours. After cooling, the reaction solution was diluted by the addition of 200 ml of ethyl acetate and then extracted exhaustively with 15% hydrochloric acid. The combined extracts were neutralized with potassium carbonate and extracted several times with chloroform, and the combined chloroform extracts were evaporated to dryness in vacuo. By recrystallization from ethyl acetate, colorless crystals were obtained, m.p.: 203°-204° C. Yield: 1.2 gm (23% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:17]#[C:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:3]=3)=[N:19][CH:20]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(Br)c3)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(-c4ccccn4)c3)nc2)cc1

Procedure:
30 mg (0.24 mmol) pyridine-3-boric acid are added to a solution of 115 mg (0.24 mmol) 2-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine (see Example 3.7), 0.5 mL (1.00 mmol) of a 2 M Na2CO3 solution and 15 mg (0.24 mmol) tetrakis-triphenylphosphane-palladium in 1 mL 1,4-dioxane and 0.3 mL methanol. The reaction mixture is refluxed for 6 h. After filtration the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 1:1:0.1).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9]1.C(O)(=O)C.[NH4+:27].[Cl-:28]>CO>[Cl-:28].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH2:27])=[NH2+:18])=[N:9]1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ccccc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=[NH2+])c1nn(Cc2ccccc2F)c2ccccc12
Temperature: 40 °C
Reaction time: 22 h

Procedure:
A sodium methoxide solution, which had been prepared from 190 mg (8.26 mmol) of NaOMe and 30 ml of abs. methanol, was added to a solution of 20.0 g (97.7 mmol) of 1-(2-fluorobenzyl)-3-cyanoindazole (from Example IX) in 200 ml of methanol, and the mixture was stirred at 40° C. for 22 h. After addition of 0.46 ml of acetic acid and 4.30 g of NH4Cl, the mixture was stirred at 40° C. for another 24 h and subsequently concentrated to dryness using a rotary evaporator. The residue was taken up in acetone and the remaining precipitate was filtered off with suction, giving, after drying under high vacuum, the product in the form of a light-beige powder.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Yield: 106.1 %

Procedure:
2 g of L-phenylalanine was dissolved in 30 ml of 50% acetic acid, and high pressure hydrogenation was conducted (hydrogen pressure: 50 kg/cm2, 40-70° C., two hours) by an addition of 200 mg of platinum oxide. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.2 g of L-cyclohexylalanine as colorless needles.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:13]([OH:14])=[CH:12][C:11]2[O:15][C:16]3[C:22](=[N:23][C:10]=2[CH:9]=1)[CH:21]=[CH:20][C:18](=[O:19])[CH:17]=3.C(=O)([O-])[O-].[K+].[K+].O>COCCOCCN(CCOCCOC)CCOCCOC.O1CCOCC1>[CH3:5][O:14][C:13]1[CH:8]=[CH:9][C:10]2[N:23]=[C:22]3[C:16]([O:15][C:11]=2[CH:12]=1)=[CH:17][C:18](=[O:19])[CH:20]=[CH:21]3
Reactant: COS(=O)(=O)OC
Reactant: O=c1ccc2nc3ccc(O)cc3oc-2c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2nc3ccc(=O)cc-3oc2c1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
12.1 ml of dimethyl sulphate were added at room temperature while stirring well to a suspension of 20.0 g (85.0 mmol) of resorufin, 17.6 g of freshly powdered potassium carbonate and 10 drops of tris-[2-(2-methoxyethoxy)ethyl]amine in 150 ml of dioxan. The reaction mixture was subsequently stirred at 100° for 2 hours, cooled and then treated with 150 ml of water. The solid was filtered off, washed with water and dried over phosphorus pentoxide. 11.5 g (59.5%) of resorufin methyl ether of m.p. 240°-244° (dec.) were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CN=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccccn1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccn3)c(-c3ccc(Cl)cc3)c2CC1
Agent: Cl
Product: Clc1ccc(-c2nn(Cc3ccccn3)c3c2CCNCC3)cc1
Yield: 7.4 %

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) using 2-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-pyridin-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H19ClN4, 338.13; found, m/z 339.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H), 2.93-2.87 (m, 4H), 2.76-2.74 (m, 4H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)c3)c3cccnc32)cc1
Yield: 68 %

Procedure:
A mixture of azaindole 3 (80 mg, 0.23 mmol), 2-chloropyridine-4-boronic acid (41 mg, 0.27 mmol), Pd(Ph3P)4 (20 mg, 0.11 mmol) and 2 M sodium carbonate (0.34 mL, 0.68 mmol) in 2 mL of DME was microwaved on high at 160° C. for under nitrogen for 15 minutes. Diluted with ethyl acetate and the organic phase washed with water and brine then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexanes) to give 60 mg (68%) of the desired product 14. 1H NMR CDCl3 8.6 (d, 2H), 8.1 (m, 4H), 7.25 (m, 5H), 2.5 (s, 3H). The 2-chloropyridine could be displaced, for example, with benzylamine in a microwave reaction at 250° C. for 30 min followed by deprotection to give compound 15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2C=CC=[CH:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:51][CH:52]([CH3:57])[CH3:53])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)N
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isopropylamine (7.03 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.4 mg, 48.5%). LC-MS m/z 615 (M+H)+.